CD44V6-DERIVED CYCLIC PEPTIDES FOR TREATING CANCERS AND ANGIOGENESIS RELATED DISEASES

Abstract

The present invention relates to compounds, pharmaceutical compositions and methods for treating different forms of cancer and angiogenesis related diseases using cyclic peptides.

Claims

1. A compound comprising: a cyclic peptide comprising at least (a) an amino acid X.sub.1 being selected from the group consisting of the amino acids A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y, further (b) an amino acid sequence R-W-H, and further (c) an amino acid X.sub.11 being selected from the group consisting of the amino acids A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y, or a peptidomimetic thereof, or a cyclic peptide comprising at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein the amino acid X.sub.1 is selected from the group consisting of the amino acids A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y, wherein the amino acids X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.11, X.sub.12, X.sub.13 and X.sub.14 are independently selected from the group consisting of the amino acids A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y, and wherein X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.12, X.sub.13 and X.sub.14 are optionally present in the amino acid sequence, or a peptidomimetic thereof, the compound comprising a chemical bond between two adjacent amino acids of the cyclic peptide which is not a chemical bond between the N-terminus of a first amino acid and the C-terminus of a second amino acid of the two adjacent amino acids.

2. The compound of claim 1, wherein the amino acid X.sub.1 is an amino acid having an NH.sub.2 group in the amino acid side chain, such as the amino acids K, R, N, or Q, and/or wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids with negatively charged side chains such as the amino acid E or D, or amino acids with non-polar side chains such as the amino acids A, V, L or I, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids with an NH.sub.2 group in the amino acid side chain, such as the amino acids K, R, N, or Q, and amino acids with non-polar side chains, such as the amino acids A, V, L or I, wherein X.sub.4 is optionally present and optionally selected from the group consisting of amino acids with non-polar or non-charged side chains and aromatic ring structures, such as the amino acids F, W, or Y, and amino acids with non-polar side chains, such as the amino acids A, V, L or I, wherein X.sub.5 is optionally present and optionally selected from the group consisting of amino acids with non-polar or non-charged side chains and aromatic rings structures, such as the amino acids F, W, or Y, and amino acids with non-polar side chains, such as the amino acids A, V, L or I, wherein X.sub.6 is optionally present and optionally selected from the group consisting of the amino acid G and amino acids with non-polar side chains, such as the amino acids A, V, L or I, wherein X.sub.7 is optionally present and optionally selected from the group consisting of amino acids with an NH.sub.2 group in the side chain, such as the amino acids K, R, N or Q, and amino acids with non-polar side chains, such as the amino acids A, V, L or I, wherein X.sub.11 is selected from the group consisting of amino acids with negatively charged side chains, such as the amino acid E or D, and amino acids with non-polar side chains, such as the amino acids A, V, L or I, wherein X.sub.12 is optionally present and optionally selected from the group consisting of the amino acid G and amino acids with non-polar side chains such as the amino acids A, V, L or I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids with non-polar or non-charged side chains and aromatic rings structures, such the amino acids F, W or Y, and amino acids with non-polar side chains, such as the amino acids A, V, L or I, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids with an NH.sub.2 group in the side chain, such as the amino acids K, R, N or Q, and amino acids with non-polar side chains, such as the amino acids A, V, L or I.

3. The compound of claim 1, wherein X.sub.1 is selected from the group consisting of K, R, N and Q, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.4 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.5 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.6 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.11 is present and optionally the amino acid E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q.

4. The compound of claim 1, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N and Q, preferably the amino acid K, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.4 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.5 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.6 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.11 is present and the amino acid E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, or a peptidomimetic thereof.

5. The compound of claim 1, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N and Q, preferably the amino acid K, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.4 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.5 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.11 is present and the amino acid E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, or a peptidomimetic thereof.

6. The compound of claim 1, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably the amino acid K, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.4 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.5 is present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is the amino acid E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, or a peptidomimetic thereof.

7. The compound of claim 1, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N and Q, preferably the amino acid K, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.4 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 is present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.11 is present and optionally E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, or a peptidomimetic thereof.

8. The compound of claim 1, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably the amino acid K, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.4 is present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.5 present and is optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.11 is present and optionally E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, or a peptidomimetic thereof.

9. The compound of claim 1, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N and Q, preferably K, wherein X.sub.2 is present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.4 is present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.5 is present and is optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.11 is present and optionally the amino acid E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, or a peptidomimetic thereof.

10. The compound of claim 1, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N and Q, preferably the amino acid K, wherein X.sub.2 is present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is present and is optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.4 is present and is optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.5 is present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.6 is present and is optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.11 is optionally the amino acid E or D, wherein X.sub.12 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, or a peptidomimetic thereof.

11. The compound of claim 1, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N and Q, preferably the amino acid K, wherein X.sub.2 is present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is present and is optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.4 is present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.5 is present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.11 is present and optionally the amino acid E or D, wherein X.sub.12 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is present and optionally selected from the group consisting of amino acids F, W and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N and Q, or a peptidomimetic thereof.

12. The compound of claim 1, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N and Q, preferably the amino acid K, wherein X.sub.2 is present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is present and is optionally selected from the group consisting of amino acids K, R, N and Q, wherein X.sub.4 is present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.5 is present and optionally selected from the group consisting of amino acids F, W and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is present and optionally the amino acid E or D, wherein X.sub.12 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is present and optionally selected from the group consisting of amino acids F, W and Y, and wherein X.sub.14 is present and is optionally selected from the group consisting of amino acids K, R, N, and Q, or a peptidomimetic thereof.

13. The compound of claim 1, wherein X.sub.1 is selected from the group consisting of the amino acids K, R, N, and Q, preferably the amino acid K, wherein X.sub.2, if present, is selected from the group consisting of amino acids E and D, wherein X.sub.3, if present, is selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4, if present, is selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5, if present, is selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6, if present, is selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7, if present, is selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is the amino acid D or E, wherein X.sub.12, if present, is selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13, if present, is selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14, if present, is selected from the group consisting of amino acids K, R, N, and Q.

14. The compound of claim 1, wherein X.sub.1 is the amino acid K, wherein X.sub.2, if present, is the amino acid E, wherein X.sub.3, if present, is the amino acid Q, wherein X.sub.4, if present, is the amino acid W, wherein X.sub.5, if present, is the amino acid F, wherein X.sub.6, if present, is the amino acid G, wherein X.sub.7, if present, is the amino acid N, wherein X.sub.11 is the amino acid E, wherein X.sub.12, if present, is the amino acid G, wherein X.sub.13, if present, is the amino acid Y, and wherein X.sub.14, if present, is the amino acid R.

15. The compound of claim 1, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.6-X.sub.7-R-W-H-X.sub.11, wherein the amino acid X.sub.1 is selected from the group consisting of the amino acids K, R, N, or Q, preferably X.sub.1 is the amino acid K, wherein the amino acid X.sub.6 is optionally present and selected from the group consisting of amino acids G, A, V, L and I, preferably X.sub.6 is the amino acid G, wherein X.sub.7 is optionally present and selected from a group consisting of amino acids K, R, N, and Q, preferably X.sub.7 is N, and wherein X.sub.11 is the amino acid D or E, preferably X.sub.11 is the amino acid E, or a peptidomimetic thereof, the compound comprising a chemical bond between two adjacent amino acids of the cyclic peptide which is not a chemical bond between the N-terminus of a first amino acid and the C-terminus of a second amino acid of the two adjacent amino acids or the cyclic peptide comprising a chemical bond selected from the group consisting of a chemical bond between an N-terminal amino group of an amino acid and an amino acid side chain, a chemical bond between a C-terminal carboxyl group of an amino acid and an amino acid side chain, and a chemical bond between an amino acid side chain of a first amino acid of the cyclic peptide and an amino acid side chain of a second amino acid of the cyclic peptide.

16. The compound of claim 1, wherein the cyclic peptide comprises, optionally consists of, the amino acid sequence K-R-W-H-E (SEQ ID No.: 34), K-N-R-W-H-E (SEQ ID No.: 35), K-G-N-R-W-H-E (SEQ ID No: 36), or a peptidomimetic thereof.

17. The compound of claim 1, wherein said peptide does not comprise the amino acid sequence N-R-W-H-E (SEQ ID No.: 2), the amino acid sequence K-R-W-H-E and a DOTA modification, the amino acid sequence K-G-N-R-W-H-E-G, the amino acid sequence K-E-Q-W-F-G-N-R-W-H-E-G-Y-R (SEQ ID No.: 6), or a peptidomimetic thereof.

18. The compound of claim 1, wherein the cyclic peptide or peptidomimetic thereof comprises a modification.

19. The compound of claim 18, wherein the modification comprises an amino acid, amino acid derivative, a lipophilic modification, or an aromatic hydrophobic modification, optionally the modification comprises phenyl acetic acid or 3-indole acetic acid.

20. The compound of claim 18, wherein the modification is not DOTA or a myristoyl group.

21. The compound of claim 1, wherein the chemical bond between the two adjacent amino acids involves the amino acid side chain of at least one of said two adjacent amino acids.

22. The compound of claim 1, wherein the cyclic peptide comprises a chemical bond selected from the group consisting of a chemical bond between an N-terminal amino group of an amino acid and an amino acid side chain, a chemical bond between a C-terminal carboxyl group of an amino acid and an amino acid side chain, and a chemical bond between an amino acid side chain of a first amino acid of the peptide and an amino acid side chain of a second amino acid of the peptide.

23. The compound of claim 1, wherein the cyclic peptide comprises a chemical bond selected from the group consisting of a chemical bond between an N-terminal amino group of an amino acid and a carboxyl group of an amino acid side chain, preferably of the amino acids E or D, a chemical bond between a C-terminal carboxyl group of an amino acid and an amino group of an amino acid side chain, preferably of the amino acids K, R, N or Q, and a chemical bond between an amino group of an amino acid side chain of a first amino acid of the peptide, preferably of the amino acids K, R, N or Q, and a carboxyl group of an amino acid side chain of a second amino acid of the peptide, preferably of the amino acids E or D.

24. The compound of claim 1, wherein the peptide comprises the amino acid sequence K-R-W-H-E (SEQ ID No.: 34), K-N-R-W-H-E (SEQ ID No.: 35) or K-G-N-R-W-H-E (SEQ ID No.: 36), comprising a chemical bond selected from the group consisting of a chemical bond between an N-terminal amino group of an amino acid and an amino acid side chain, optionally a carboxyl group of an amino acid side chain, a chemical bond between a C-terminal carboxyl group of an amino acid and an amino acid side chain, optionally an amino group of an amino acid side chain, and a chemical bond between an amino acid side chain of a first amino acid of the peptide and an amino acid side chain of a second amino acid of the peptide, optionally between a carboxyl group of the amino acid side chain of the first amino acid and an amino group of the amino acid side chain of the second amino acid.

25. The compound of claim 23, wherein the peptide comprises the amino acid sequence K-R-W-H-E (SEQ ID No.: 34) and comprises a chemical bond between an N-terminal amino group of a first amino acid, preferably of the amino acid K, and an amino acid side chain, preferably a carboxyl group of an amino acid side chain, of a second amino acid, preferably of the amino acid E.

26. The compound of claim 23, wherein the peptide comprises the amino acid sequence as depicted in SEQ ID No.: 35 and comprises a chemical bond between an N-terminal amino group of a first amino acid, preferably of the amino acid K, and an amino acid side chain, preferably a carboxyl group of an amino acid side chain, of a second amino acid, preferably of the amino acid E.

27. The compound of claim 23, wherein the peptide comprises the amino acid sequence as depicted in SEQ ID No.: 36 and comprises a chemical bond between an N-terminal amino group of a first amino acid, preferably of the amino acid K, and an amino acid side chain, preferably a carboxyl group of an amino acid side chain, of a second amino acid, preferably of the amino acid E.

28. The compound of claim 23, wherein the peptide comprises the amino acid sequence K-R-W-H-E (SEQ ID No.: 34) and comprises a chemical bond between an amino acid side chain, preferably the amino group of an amino acid side chain, of a first amino acid, preferably of the amino acid K, and the C-terminal carboxyl group of a second amino acid, preferably of E.

29. The compound of claim 1, wherein the amino acid side chain is the amino acid side chain of an amino acid selected from the group consisting of the amino acids E, D, K, R, N and Q.

30. The compound of claim 1, wherein the chemical bond comprises the carboxyl group of an amino acid side chain of an amino acid E or D and/or wherein the chemical bond comprises the amino group of an amino acid side chain of any one of the amino acids K, R, N or Q.

31. The compound of claim 1, wherein the amino acid side chain is modified or truncated.

32. The compound of claim 1, wherein at least one amino acid of the cyclic peptide is a D-amino acid.

33. The compound of claim 32, wherein 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids are D-amino acids.

34. The compound of claim 32, wherein at least one amino acid of the amino acid sequence R-W-H is a D-amino acid.

35. The compound of claim 34, wherein at least W is a D-amino acid.

36. The compound of claim 34, wherein at least H is a D-amino acid.

37. The compound of claim 34, wherein at least R is a D-amino acid.

38. The compound of claim 34, wherein W is a D-amino acid or wherein R is a D-amino acid, or wherein H is a D-amino acid.

39. The compound of claim 34, wherein the peptide comprises the amino acid sequence K-R-W-H-E (SEQ ID No.: 34), K-N-R-W-H-E (SEQ ID No.: 35) or K-G-N-R-W-H-E (SEQ ID NO.: 36), comprising a chemical bond selected from the group consisting of a chemical bond between an N-terminal amino group of a first amino acid and an amino acid side chain, optionally a carboxyl group of an amino acid side chain, of a second amino acid, a chemical bond between a C-terminal carboxyl group of a first amino acid and an amino acid side chain, optionally an amino group of an amino acid side chain, of a second amino acid, and a chemical bond between an amino acid side chain of a first amino acid of the peptide and an amino acid side chain of a second amino acid of the peptide, optionally between a carboxyl group of the amino acid side chain of the first amino acid and an amino group of the amino acid side chain of the second amino acid, wherein at least one amino acid is a D-amino acid, preferably at least one amino acid of the amino acid sequence R-W-H is a D-amino acid.

40. The compound of claim 1, wherein the peptide comprises the amino acid sequence K-R-W-H-E (SEQ ID No.: 34) comprising a chemical bond between an N-terminal amino group of a first amino acid and an amino acid side chain, preferably a carboxyl group of an amino acid side chain, of a second amino acid, preferably comprising a chemical bond between the N-terminal amino group of K and the carboxyl group of the amino acid side chain of E, wherein at least one amino acid is a D-amino acid, preferably at least one amino acid of the amino acid sequence R-W-H is a D-amino acid, preferably the amino acid W is a D-amino acid.

41. The compound of claim 1, wherein the peptide comprises or has the amino acid sequence K-R-W-H-E (SEQ ID No.: 34) and comprises a chemical bond between the N-terminal amino group of the amino acid K and the carboxyl group of the amino acid side chain of the amino acid E, and wherein the amino acid W is a D-amino acid.

42. The compound of claim 1, wherein the peptide comprises the amino acid sequence as depicted in SEQ ID No.: 35 and comprises a chemical bond between an N-terminal amino group of a first amino acid, preferably of the amino acid K, and an amino acid side chain, preferably a carboxyl group of an amino acid side chain of a second amino acid, preferably of the amino acid E, wherein at least one amino acid is a D-amino acid.

43. The compound of claim 1, wherein the peptide comprises the amino acid sequence as depicted in SEQ ID No.: 36 and comprises a chemical bond between an N-terminal amino group of a first amino acid, preferably of the amino acid K, and an amino acid side chain, preferably a carboxyl group of an amino acid side chain of a second amino acid, preferably of the amino acid E, wherein the amino acid H is a D-amino acid.

44. The compound of claim 1, wherein the peptide comprises the amino acid sequence K-R-W-H-E (SEQ ID No.: 34) and comprises a chemical bond between an amino acid side chain, preferably the amino group of an amino acid side chain of a first amino acid, preferably of the amino acid K, and the C-terminal carboxyl group of a second amino acid, preferably of the amino acid E, wherein the amino acid R is a D-amino acid.

45. The compound of claim 1, wherein the peptide is selected from the group consisting of a peptide having the amino acid sequence K-R-W-H-E (SEQ ID No.: 34), comprising a chemical bond between the N-terminal amino group of the amino acid K and the carboxyl group of the amino acid side chain of the amino acid E, and wherein the amino acid W is a D-amino acid, a peptide having the amino acid sequence as depicted in SEQ ID No.: 35, comprising a chemical bond between the N-terminal amino group of the amino acid K and the carboxyl group of the amino acid side chain of the amino acid E, a peptide comprising the amino acid sequence SEQ ID No.: 36, comprising a chemical bond between the N-terminal amino group of the amino acid K and the carboxyl group of the amino acid side chain of the amino acid E, wherein the amino acid H is a D-amino acid, and a peptide comprising the amino acid sequence K-R-W-H-E (SEQ ID No.: 34), comprising a chemical bond between the amino group of the amino acid side chain of the amino acid K and the C-terminal carboxyl group of the amino acid E, wherein the amino acid R is a D-amino acid.

46. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

47. The compound of claim 1, wherein the compound is formulated for intravenous, oral, nasal, or subcutaneous administration.

48. The compound of claim 1, wherein the compound is administered in combination with a cytotoxic compound, an immunopharmaceutical, an antibody against a receptor tyrosine kinase (RTK) and/or a chemotherapeutic agent, preferably the compound of the invention is administered in combination with a compound selected from the group consisting of an epidermal growth factor receptor (EGFR) inhibitor, preferably selected from the group consisting of gefitinib, erlotinib, lapatinib, cetuximab, panitumumab, vandetanib and mixtures thereof, an hepatocyte growth factor receptor (HGF/c-Met) inhibitor, preferably selected from the group consisting of ficlatuzumab, crizotinib, tivantinib, cabozantinib, capmatinib, MGCD265, volitinib, MK8033, MK-2461, and mixtures thereof, a programmed cell death protein 1 (PD-1) inhibitor, preferably selected from the group consisting of nivolumab/BMS-936558, lambrolizumab, pidilizumab, AMP-224, pembrolizumab and mixtures thereof, a programmed death-ligand 1 (PD-L1) inhibitor, preferably selected from the group consisting of BMS-936559, RG7446/MPDL3280A, MEDI4736, MSB0010718C/Avelumab and mixtures thereof, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, preferably ipilimumab, a vascular endothelial growth factor receptor (VEGFR) inhibitors, preferably selected from the group consisting of bevacicumab, pazopanib, sorafenib, sunitinib, axitinib, ponatinib, regorafenib, vandetanib, cabozantinib, lenvatinib, ramucirumab and mixtures thereof, a chemotherapeutic agent, preferably selected from the group consisting of an alkylating agent, preferably selected from the group consisting of a nitrogen mustard, such as mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide and melphalan, nitrosourea, such as streptozocin, carmustine (BCNU) and lomustine, an alkyl sulfonate, such as busulfan, a triazine, such as dacarbazine (DTIC) and temozolomide, an ethylenimine, such as thiotepa and altretamine (hexamethylmelamine), and mixtures thereof, a platinum drug, preferably selected from the group consisting of cisplatin, carboplatin, oxalaplatin and a mixture thereof, an antimetabolite, preferably selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, and mixtures thereof, an taxane, an eribulin, folfirinox, folfox, an anthracycline, preferably selected from the group consisting of daunorubicin, doxorubicin, epirubicin, idarubicin and a mixture thereof; and a mixture thereof; and combinations thereof.

49. The compound of claim 1 for use as a medicament.

50. The compound of claim 1 for use in treating a disease selected from the group consisting of cancer, an angiogenesis related disease, a disease from the field of ophthalmology, diseases associated with an increased invasive potential of cells, and inflammatory disorders in a human being.

51. The compound of claim 50, wherein the cancer is a metastasizing cancer.

52. The compound of claim 50, wherein the disease is selected from the group consisting of estrogen receptor-dependent breast cancer, estrogen receptor-independent breast cancer, hormone receptor-dependent prostate cancer, hormone receptor-independent prostate cancer, brain cancer, renal cancer, colon cancer, familial adenomatous polyposis (FAP), colorectal cancer, pancreatic cancer, bladder cancer, esophageal cancer, stomach cancer, genitourinary cancer, gastrointestinal cancer, uterine cancer, ovarian cancer, astrocytomas, gliomas, skin cancer, squamous cell carcinoma, Keratoakantoma, Bowen disease, cutaneous T-Cell Lymphoma, melanoma, basal cell carcinoma, actinic keratosis; ichtiosis; acne, acne vulgaris, sarcomas, Kaposi's sarcoma, osteosarcoma, head and neck cancer, small cell lung carcinoma, non-small cell lung carcinoma, leukemia, lymphomas and/or other blood cell cancers, thyroid resistance syndrome, diabetes, thalassemia, cirrhosis, protozoal infection, rheumatoid arthritis, rheumatoid spondylitis, all forms of rheumatism, osteoarthritis, gouty arthritis, multiple sclerosis, insulin dependent diabetes mellitus, non-insulin dependent diabetes, asthma, rhinitis, uveithis, lupus erythematoidis, ulcerative colitis, Morbus Crohn, inflammatory bowel disease, chronic diarrhea, psoriasis, atopic dermatitis, bone disease, fibroproliferative disorders, atherosclerosis, aplastic anemia, DiGeorge syndrome, Graves' disease, epilepsia, status epilepticus, alzheimer's disease, depression, schizophrenia, schizoaffective disorder, mania, stroke, mood-incongruent psychotic symptoms, bipolar disorder, affective disorders, meningitis, muscular dystrophy, multiple sclerosis, agitation, cardiac hypertrophy, heart failure, reperfusion injury, diabetic retinopathy, age-related macular degeneration, allergic diseases, e.g. asthma, due to an increase in eosinophil granulocytes, rejection of heart transplantation, and obesity in a human being.

53. The compound of claim 50, wherein said cancer shows expression of CD44v6.

54. The compound of claim 50, wherein said cancer is classifiable as Stage III or Stage IV according to the TNM anatomic/prognostic group system of the cancer staging system of the American Joint Committee on Cancer.

55. The compound of claim 50, wherein said cancer is classifiable as Stage IV according to the TNM anatomic/prognostic group system of the cancer staging system of the American Joint Committee on Cancer.

56. The compound for use of claim 50, wherein said cancer is a metastasizing cancer selected from the group consisting of metastasizing forms of Hodgkin lymphoma, colorectal cancer, cervical cancer, lung cancer, skin cancer such as squamous cell cancer or basal cell carcinoma, head and neck cancer, gastric cancer, pancreatic cancer, head and neck squamous cell cancer, and breast cancer.

57. The compound for use of claim 50 wherein said cancer is a metastasizing cancer selected from the group consisting of metastasizing forms of Hodgkin lymphoma, colorectal cancer, cervical cancer, lung cancer, skin cancer such as squamous cell cancer or basal cell carcinoma, head and neck cancer, gastric cancer, pancreatic cancer, and breast cancer, wherein said metastasizing cancer is classifiable as Stage IV according to the TNM anatomic/prognostic group system of the cancer staging system of the American Joint Committee on Cancer, and wherein said metastasizing cancer shows expression of CD44v6.

Description

FIGURE LEGENDS

[0101] FIG. 1 provides structural information on the cyclic peptides of the present invention. It further shows the structure of the pentapeptide K-R-W-H-E and possible abbreviations depending on the kind of chemical bonds which have been used in the method of producing for the cyclization step. For example, the first syllable gives the chemical group on the N-terminal side of the tripeptide R-W-H which participates in cyclization: “al” (alpha) denotes the N-terminal amino group and “ep” (epsilon) the amino group of the amino acid side chain of the amino acid K. The Greek letter is thus the position in the amino acid side chain where the reaction occurs. Greek letters are commonly used to number the carbon atoms of an amino acid side chains starting from the alpha carbon atom being the carbon atom in the peptide backbone. The second syllable gives the chemical group which participates in cyclisation on the C-terminal site of the tripeptide R-W-H: “al” (alpha) denotes the C-terminal carboxyl group and “ga” (gamma) the carboxyl group of the amino acid side chain of the amino acid E. The number in the abbreviations indicates the length of the peptide according to the list given in FIG. 1.

[0102] FIG. 2: Exemplary cyclic peptides according to the present invention and focuses in particular on modified peptides.

[0103] FIG. 3: A cyclic CD44v6 5mer (alga1, cf. FIG. 1) and a cyclic CD44v6 5mer containing a D-amino acid at position 3 (D3alga1, cf. FIGS. 1 and 9) block activation of c-Met and Erk. A: alga1; B: D3alga1. The first row shows the activation status of Met, below the loading control of total Met protein. The third row shows the activation status of the Erk, a downstream target of the Met pathway, below total Erk protein amount is presented. “ctrl peptide”=control peptide N-A-A-A-E

[0104] FIG. 4: Cyclic CD44v6 5mer containing a D-amino acid at positions 1, 2 and 3, respectively (D1alga1, D2alga1, D3alga1), blocks activation of c-Met and Erk. The first row shows the activation status of Met, below the loading control of total Met protein. The third row shows the activation status of the Erk, a downstream target of the Met pathway, below total Erk protein amount is presented. “ctrl peptide”=control peptide N-A-A-A-E

[0105] FIG. 5: A: Wound healing assay. B: Quantitative evaluation of the wound healing assay with the computer program ImageJ. “ctrl pep”=control peptide N-A-A-A-E

[0106] FIG. 6: Side by side comparison of the human CD44v6 14mer (V6 14MER), alga1 and D3alga1 for their effect on tumor growth inhibition and inhibition on tumor metastasis. A: Inhibition of tumor growth. Bar chart representing the average tumor volume of each treatment group. Significance was calculated using Student's t test: ***p<0.001. B: Inhibition of metastatic spreading to the liver. Bar chart representing the average tumor number of metastases of each treatment group. Significance was calculated using Student's t test: ***p<0.001. “ctrl pep”=control peptide N-A-A-A-E

[0107] FIG. 7: Side by side comparison of the human CD44v6 14mer (V614MER), alga1 and D3alga 1 for their effect on regression of already established metastases. A: Inhibition of tumor growth. Bar chart representing the average tumor volume of each treatment group. Significance was calculated using Student's t test: ***p<0.001. B: Regression of established liver metastases. Bar chart representing the average tumor number of metastases of each treatment group. Significance was calculated using Student's t test: ***p<0.001. “ctrl pep”=control peptide N-A-A-A-E.

[0108] FIG. 8: Comparison of the tumor accumulation of the v6 14-mer linear peptide and alga1 and D3alga1 after labelling with .sup.68Ga using PET imaging. Each image shows a coronar view of the tumor xenograft of L3.6pl cells in comparison to the kidneys (left, kidneys appear as two black blots, xenograft on the right for v6 14mer, on the left for alga1 and D3alga1), in comparison to the bladder (middle, bladder appears as one black blot, xenograft on the right of the bladder for v6 14mer, on the left of the bladder for alga1 and D3alga1), and in an isolated view of the xenograft (right).

[0109] FIG. 9: Structure of D3 alga1 (cf. FIG. 1, cyclic K-R-W-H-E, wherein cyclisation is via the N-terminal amino group and the carboxyl group in the amino acid side chain of E, and wherein W is a D-amino acid).

[0110] FIG. 10: Structure of D6-alga3 (cy[αKGNRWHEγ], wherein cyclisation is via the N-terminal amino group of K and the carboxyl group in the amino acid side chain of E, and wherein H is a D-amino acid).

[0111] FIG. 11: Structure of D2-epal1 (cy[εKRWHEα]γ], wherein cyclisation is via the amino group in the amino acid side chain of K and the C-terminal carboxyl group of E, and wherein R is a D-amino acid).

[0112] FIG. 12: Structure of alga2 (cy[αKNRWHEγ], wherein cyclisation is via the N-terminal amino group of K and the carboxyl group in the amino acid side chain of E).

[0113] FIG. 13: List of preferred D-amino acid containing cyclic peptides of the invention which comprise at least one non-peptide bond between two adjacent amino acids in the circle. The sequence information is to be read as follows: the part in square brackets indicates the two adjacent amino acids which are connected via a chemical bond which is not a peptide bond. The Greek letters give further information on the chemical bond between the two adjacent amino acids. For example, [εKγE] in the sequence of D2-apga-1 denotes that the cyclic peptides comprises a bond between the amino group at ε-position in the amino acid side chain of lysine (K) and the carboxyl group in the γ-position in the amino acid side chain of glutamic acid (E) (cf. FIG. 1). “cy” denotes that the peptide is a cyclic peptide. In round brackets, the amino acid sequence of the cyclic peptide is given. Here, a lowercase letter indicates that the amino acid is a D-amino acid, while capital letters indicate a L-amino acid. Hence, D2-apga-1 contains the D-amino acid arginine (R). Regarding the indicated name of the peptides, D denotes that at least one D-amino acid is present. The Figure after the letter “D” indicates the position of the D-amino acid in the sequence starting with the first K on the N-terminal side of the motif R-W-H as the amino acid at position 1. The first syllable of the second part of the name indicates the chemical group on the N-terminal side of the central motif sequence R-W-H which participates in the chemical bond which is not a peptide bond: “al” (alpha) denotes the N-terminal amino group and “ep” (osilon) the amino group of the amino acid side chain of K. The Greek letter is thus the position in the amino acid side chain where the cyclisation reaction occurs and which participates in the chemical bond which is not a peptide bond. The second syllable gives the chemical group which participates in cyclisation on the C-terminal site of the tripeptide R-W-H: “al” (alpha) as second syllable is the C-terminal carboxyl group and “ga” (gamma) the carboxyl group of the amino acid side chain of the amino acid E. The number in the abbreviations indicates the length of the peptide according to the list as also given in FIG. 1. Hence, “1” indicates a “5” mer as the minimal peptide length, “2” indicates a 6 mer, “3” indicates a 7 mer and so forth.

[0114] FIG. 14: List of cyclic peptides not comprising a D-amino acid. The names and sequences are indicated as in the Figure legend of FIG. 13.

[0115] FIG. 15: Results of the wound healing assay according to Example 9, wherein the blocking efficiency of the indicated peptides is tested.

DETAILED DESCRIPTION OF THE INVENTION

[0116] Before the invention is described in detail with respect to some of its preferred embodiments, the following general definitions are provided.

[0117] The present invention as illustratively described in the following may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein.

[0118] The present invention will be described with respect to particular embodiments and with reference to certain figures but the invention is not limited thereto but only by the claims.

[0119] Where the term “comprising” is used in the present description and claims, it does not exclude other elements. For the purposes of the present invention, the term “consisting of” is considered to be a preferred embodiment of the term “comprising of”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group, which preferably consists only of these embodiments.

[0120] For the purposes of the present invention, the term “obtained” is considered to be a preferred embodiment of the term “obtainable”. If hereinafter e.g. an antibody is defined to be obtainable from a specific source, this is also to be understood to disclose an antibody, which is obtained from this source.

[0121] Where an indefinite or definite article is used when referring to a singular noun, e.g. “a”, “an” or “the”, this includes a plural of that noun unless something else is specifically stated. The terms “about” or “approximately” in the context of the present invention denote an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value of ±20%, preferably ±15%, more preferably ±10%, and even more preferably ±5%.

[0122] Furthermore, the terms “first”, “second”, “third” or “(a)”, “(b)”, “(c)”, “(d)” or “(i)”, “(ii)”, “(iii)”, “(iv)” etc. and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

[0123] In case the terms “first”, “second”, “third” or “(a)”, “(b)”, “(c)”, “(d)” or “(i)”, “(ii)”, “(iii)”, “(iv)” etc. relate to steps of a method or use or assay there is no time or time interval coherence between the steps unless indicated otherwise, i.e. the steps may be carried out simultaneously or there may be time intervals of seconds, minutes, hours, days, weeks, months or even years between such steps, unless otherwise indicated in the application as set forth herein above or below.

[0124] Technical terms are used by their common sense. If a specific meaning is conveyed to certain terms, definitions of terms will be given in the following in the context of which the terms are used.

[0125] As mentioned above, the present invention is concerned with cyclic peptides or peptide compounds useful in treating metastasizing cancer in a human being. “Cyclic peptides” in the sense of the invention are according to the general knowledge in the field of protein chemistry polypeptide chains wherein the N-terminal amino group and carboxyl group of the C-terminus, the amino group of the N-terminus and an amino acid side chain, the C-terminal carboxyl group and an amino acid side chain, or two amino acid side chains are linked with a covalent bond that generates the ring or circle. Preferably, the cyclic peptides of invention are polypeptide chains wherein at least one covalent bond is selected from a chemical bond between the amino group of the N-terminus and an amino acid side chain, between the C-terminal carboxyl group and an amino acid side chain, or between two amino acid side chains.

[0126] The present invention is based to some extent on the experimental findings described hereinafter that a cyclic peptide, such as of amino acid sequence K-R-W-H-E (SEQ ID No. 34) with or without D-amino acid is capable of inhibiting metastasis in a mouse animal model. It thus seems reasonable to assume that the same efficacy can be observed in different metastasizing cancers in human, particularly where these cancers show expression of CD44v6. It was moreover shown that introducing D-amino acids in the cyclic peptide even increases the inhibitory effect of the peptide on cell migration and metastasis. Therefore, it seems reasonable to assume that a cyclic peptide as defined herein and in the claims can be used for cancers in general, preferably metastasizing cancers, angiogenesis related diseases and other related diseases. Tumors observed in the experimental section were smaller and less vascularized demonstrating the effectiveness of the cyclic peptides described herein as anti-angiogenesis reagents. Additionally, the cyclic peptides inhibited cell migration in the wound healing assay (cf. Example 5 (cf. FIG. 5).

[0127] The term “peptide” as used herein refers to any compound comprising at least the above mentioned five amino acids.

[0128] The term “compound comprising a cyclic peptide” refers to compounds which comprise a cyclic peptide optionally e.g. in the form of a pharmaceutically acceptable salt. The term equally refers to peptides which have been e.g. chemically or enzymatically modified such that the cyclic peptide comprises additional modifications as they are described hereinafter.

[0129] The term “compound comprising a peptide” or “compound comprising a cyclic peptide” and its grammatical variation such as “cyclic peptide compound” or “peptide compound” thus includes salts, preferably pharmaceutically acceptable salts of the peptides described herein. Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the peptide compounds of this invention. Representative salts and esters include the following: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, caamsylate, carbonate, citrate, dihydrochloride, methanesulfonate, ethanesulfonate, p-toluenesulfonate, cyclohexylsulfamate, quinate, edetate, edisylate, estolate, esylate, fumarate, gluconate, glutamate, glycerophophates, hydrobromide, hydrochloride, hydroxynaphthoate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, n-methylglucamine, oleate, oxalate, palmoates, pamoate (embonate), palmitate, pantothenate, perchlorates, phosphate/diphosphate, polygalacturonate, salicylates, stearate, succinates, sulfate, sulfamate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and valerate. Other salts include Ca, Li, Mg, Na, and K salts; salts of amino acids such as lysine or arginine; guanidine, diethanolamine or choline; ammonium, substituted ammonium salts or aluminum salts. The salts are prepared by conventional methods.

[0130] It is preferred that the peptide component of the invention is an isolated cyclic peptide. The term “isolated” means altered “by the hand of man” from the natural state. If an “isolated” composition or substance occurs in nature, it has been changed or removed from its original environment, or both. For example, a polynucleotide or a polypeptide naturally present in a living animal is not “isolated,” but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is “isolated”, as the term is employed herein.

[0131] It is also preferred that the cyclic peptide of the invention is in a pure state. Preferably, the peptide is ≧80% pure, preferably ≧90% pure, more preferably ≧95% pure, even more preferably ≧99% pure and particularly preferred is a pharmaceutically pure state that is greater than 99.9% pure with respect to contaminating macromolecules, particularly other peptides. It is preferred that the peptide is free of infectious and pyrogenic agents.

[0132] Preferably, a purified cyclic peptide is substantially free of other peptides. When used in this context, the term “pure” does not exclude the presence of the same peptide in alternative physical forms, such as dimers.

[0133] The peptides of the invention may be prepared by chemical synthesis or by recombinant expression in host cells. The preparation by chemical synthesis is preferred (cf. Examples 1 and 2). As protein products, compounds or any of the other peptides of the present invention are amenable to production by the technique of solution- or solid-phase peptide synthesis. The synthetic peptide synthesis approach generally entails the use of automated synthesizers and appropriate resin as solid phase, to which is attached the C-terminal amino acid of the desired peptide. Extension of the peptide in the N-terminal direction is then achieved by successively coupling a suitably protected form of the next desired amino acid, using either FMOC- or BOC-based chemical protocols typically, until synthesis is complete. Protecting groups are then cleaved from the peptide, usually simultaneously with cleavage of peptide from the resin, and the peptide is then isolated and purified using conventional techniques, such as by reversed phase HPLC using acetonitrile as solvent and tri-fluoroacetic acid as ion-pairing agent. Such procedures are generally described in numerous publications and reference may be made, for example, to Stewart and Young, “Solid Phase Peptide Synthesis,” 2nd Edition, Pierce Chemical Company, Rockford, Ill. (1984).

[0134] The term “peptidomimetic” refers to a small protein-like chain designed to mimic a corresponding peptide. Peptidomimetics can typically arise either from modification of an existing peptide, or by designing similar systems that mimic peptides, such as peptoids and β-peptides. Irrespective of the approach, the altered chemical structure is designed to advantageously adjust the molecular properties such as metabolic stability and bioavailability without negatively affecting biological activity.

[0135] Typically a peptidomimetic will have an altered backbone such as a methylated amide group instead of the amide group of a peptide bond to increase the stability of the peptidomimetic against degradation by proteases. Alternatively or in addition, the peptidomimetic may also comprise non-natural amino acids or D-enantiomers. A common theme of peptidomimetics is that the molecular changes in the backbone structure and/or in the amino acids should not have a substantial effect on the overall conformation of the peptidomimetic in comparison to the corresponding peptide in order to not negatively affect the biological activity of the peptidomimetic. Thus, a peptidomimetic is an isostere of the corresponding peptide. Preferred peptidomimetics are e.g. isosteric peptoids, which comprise poly-N-substituted glycines in the peptide bonds of the backbone. In accordance with the invention, peptidomimetic shall therefore have the same activity in the experiments described hereinafter as the peptides as described hereinafter, such as e.g. a peptide of SEQ ID NO. 1-36. The most preferred peptidomimetics are those having five amino acids such as a peptidomimetic of a peptide of SEQ ID No. 37, 6 amino acids (such as a peptidomimetic of SEQ ID NO: 35) or 7 amino acids (cf. SEQ ID NO: 36). Such peptidomimetics are preferably isosteric peptoids, which comprise poly-N-substituted glycines in the peptide bonds of the backbone.

[0136] The present invention also contemplates modified forms of cyclic peptides or peptidomimetics. Such modified forms relate e.g. to cyclic peptides or peptidomimetics which have been chemically modified at their amino acid side chains, such as by alkylation such as methylation to reduce degradation of the peptides or peptidomimetics e.g. by proteases and to increase stability thereof. Other modifications include amino acids, amino acid derivatives, or aromatic hydrophobic modifications; wherein optionally the modification comprises phenyl acetic acid or 3-indole acetic acid; acetylating, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, i.e. a cyclic peptide, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, ubiquitination and sumoylation. A typical peptidomimetic can have one or more modification, i.e. can comprise D-amino acids and have an aromatic or hydrophobic modification. Typical examples of peptidomimetics include those which have SEQ ID Nos: 1 to 36 with L- and/or D-amino acids.

[0137] Cyclization of peptides is performed by methods generally known by a person skilled in the art, such as described in Zitzmann et al. (2005, Journal of Nuclear Medicine, 46(5):782). More detailed information can also be taken from Example 1 and 2.

[0138] The compounds of the invention can also be administered in combination with cytotoxic compounds, immunopharmaceuticals, antibodies against a receptor tyrosine kinase (RTK), and/or chemotherapeutic agents, preferably the compound of the invention is administered in combination with a compound selected from the group consisting of an epidermal growth factor receptor (EGFR) inhibitor, preferably selected from the group consisting of gefitinib, erlotinib, lapatinib, cetuximab, panitumumab, vandetanib and mixtures thereof, an hepatocyte growth factor receptor (HGF/c-Met) inhibitor, preferably selected from the group consisting of ficlatuzumab, crizotinib, tivantinib, cabozantinib, capmatinib, MGCD265, volitinib, MK8033, MK-2461, and mixtures thereof, a programmed cell death protein 1 (PD-1) inhibitor, preferably selected from the group consisting of nivolumab/BMS-936558, lambrolizumab, pidilizumab, AMP-224, pembrolizumab and mixtures thereof, a programmed death-ligand 1 (PD-L1) inhibitor, preferably selected from the group consisting of BMS-936559, RG7446/MPDL3280A. MEDI4736, MSB0010718C/Avelumab and mixtures thereof, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, preferably ipilimumab, a vascular endothelial growth factor receptor (VEGFR) inhibitors, preferably selected from the group consisting of bevacicumab, pazopanib, sorafenib, sunitinib, axitinib, ponatinib, regorafenib, vandetanib, cabozantinib, lenvatinib, ramucirumab and mixtures thereof, a chemotherapeutic agent, preferably selected from the group consisting of an alkylating agent, preferably selected from the group consisting of a nitrogen mustard, such as mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide and melphalan, nitrosourea, such as streptozocin, carmustine (BCNU) and lomustine, an alkyl sulfonate, such as busulfan, a triazine, such as dacarbazine (DTIC) and temozolomide, an ethylenimine, such as thiotepa and altretamine (hexamethylmelamine), and mixtures thereof, a platinum drug, preferably selected from the group consisting of cisplatin, carboplatin, oxalaplatin and a mixture thereof, an antimetabolite, preferably selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, and mixtures thereof, an taxane, an eribulin, folfirinox, folfox, an anthracycline, preferably selected from the group consisting of daunorubicin, doxorubicin, epirubicin, idarubicin and a mixture thereof; and a mixture thereof; and combinations thereof. In addition or alternatively preferred modified forms of peptides or peptidomimetics in accordance with the invention include e.g. chemically or enzymatically modified forms thereof which have improved biological properties such as improved solubility, absorption, biological half-life, etc. The modifications may alternatively decrease the toxicity of the molecule, eliminate or attenuate any undesirable side effect of the molecule, etc. Modifications which increase e.g. the biological half-life include pegylation, hesylation, pasylation, glycosylation with glycosyl structure having sialic acid residues at their end, etc.

[0139] Below it is set out how the compounds in accordance with the present invention, i.e. the cyclic peptides, peptidomimetics thereof and modified forms thereof, the pharmaceutical compositions comprising these compounds and methods making use of these compounds may be used for the treatment of cancer, an angiogenesis related disease, a disease from the field of ophthalmology, diseases associated with an increased invasive potential of cells, and inflammatory disorders in a human being, preferably metastasizing cancer in a human being. It is to be understood that, whenever reference is made in the following to the treatment of metastasizing cancer, this reference, as a preferred embodiment, always contemplates to use the cyclic peptides as described hereinafter, preferably those of SEQ ID NO:34, SEQ ID NO:35 and SEQ ID NO:36.

[0140] As can be taken from the experiments described hereinafter, the cyclic peptides used in the experiments were capable of inhibiting metastasis formation in adenocarcinoma models. As mentioned, the invention further relates to the use of compounds, pharmaceutical compositions and the application of methods as described herein for the treatment of metastasizing cancers.

[0141] Metastasizing cancers in accordance with the invention include metastasizing forms of cancers for which expression of CD44v6 has been observed on cancer tissues or can be observed upon corresponding testing e.g. with CD44v6 antibodies. Thus, in order to see whether a patient is eligible for treatment with compounds and pharmaceutical compositions as described herein, one may take a biopsy of tumor tissue and test for expression of CD44v6. If the tumor can be shown to express CD44v6 and if metastases have started to form or have already formed and maybe even spread through the body, this tumor is considered as a metastasizing cancer in accordance with the invention. Metastasizing cancers in accordance with the invention include metastasizing forms of Hodgkin lymphoma, colorectal cancer, cervical cancer, lung cancer, skin cancer such as squamous cell cancer or basal cell carcinoma, head and neck cancer, gastric cancer, pancreatic cancer, head and neck squamous cell cancer, breast cancer, and others.

[0142] Such metastasizing cancer forms of the various cancers such as Hodgkin lymphoma, colorectal cancer, cervical cancer, lung cancer, skin cancer such as squamous cell cancer or basal cell carcinoma, head and neck cancer, gastric cancer, pancreatic cancer and breast cancer can be identified according to the TNM Anatomic Stage/Prognostic Group System of the Cancer Staging Manual of the American Joint Committee on Cancer (7.sup.th edition, 2010, Springer).

[0143] Metastasizing cancers in accordance with the invention may be classified as Stage III or Stage IV cancers according to the TNM Anatomic Stage/Prognostic Group System of the Cancer Staging Manual of the American Joint Committee on Cancer (7.sup.th edition, 2010, Springer). The TNM (tumor node metastasis) staging system of the American Joint Committee on Cancer allows staging, i.e. classification of cancers by the size and extent of the primary tumor (T), the question if regional lymph nodes (N) are affected and if distant metastases can already be detected (M). This indication is then typically taken as an indication for different routes to take in treating the patient and also allows a reliable prognosis of the diseases. This is why the TNM system has become an indispensable tool for oncologists. The parameter M receives a value of 0, i.e. M0 if no distant metastases can be detected clinically although they may have started to develop. If M is set at M0, a patient depending on the values of T and N may be classified as Stage III. Thus for e.g. any T, N3 and M0, a patient may be classified as Stage III, or Stage IIIc in case of e.g. breast cancer (see page 362, Cancer Staging Manual of the American Joint Committee on Cancer (7.sup.th edition, 2010, Springer). If such a Stage III patient or a patient having the highest subclass of Stage III (such as Stage IIIC for breast cancer) additionally displays circulating tumor cells and micrometastases in the bone marrow, this will worsen the prognosis. Thus, for the purposes of the present invention a metastasizing cancer may be classifiable as Stage III according to the TNM Anatomic Stage/Prognostic Group System of the Cancer Staging Manual of the American Joint Committee on Cancer (7.sup.th edition, 2010, Springer).

[0144] Preferably, for a metastasizing cancer in accordance with the invention M is M1, i.e. that distant metastasis can be clinically detected so that such a metastasizing tumor can be classified as Stage IV according to the TNM Anatomic Stage/Prognostic Group System of the Cancer Staging Manual of the American Joint Committee on Cancer (7.sup.th edition, 2010, Springer).

[0145] It is to be understood that wherever the present invention makes reference to a metastasizing cancer, this most preferably relates to a cancer such as Hodgkin lymphoma, colorectal cancer, cervical cancer, lung cancer, skin cancer such as squamous cell cancer or basal cell carcinoma, head and neck cancer, gastric cancer, pancreatic cancer, or breast cancer, which is classified as Stage IV according to the TNM Anatomic Stage/Prognostic Group System of the Cancer Staging Manual of the American Joint Committee on Cancer (7.sup.th edition, 2010, Springer). The specific requirements for classifying each cancer according to this system, which can be found in the respective chapters of the Cancer Staging Manual of the American Joint Committee on Cancer (7.sup.th edition, 2010, Springer), see e.g. page 143 to 146 for colorectal cancer, page 241 to 250 for pancreatic cancer, page 301 to 314 for squamous cell cancer, page 347 to 376, etc.), are hereby incorporated by reference.

[0146] A particularly preferred embodiment thus refers to the use of the cyclic peptides described hereinafter, e.g. of SEQ ID NO:19-36 and most preferably of SEQ ID NO:34-36, peptidomimetics thereof or modified forms thereof, and pharmaceutical compositions comprising these compounds for the treatment of metastasizing cancers such as Hodgkin lymphoma, colorectal cancer, cervical cancer, lung cancer, skin cancer such as squamous cell cancer or basal cell carcinoma, head and neck cancer, gastric cancer, pancreatic cancer, or breast cancer, which are classifiable as Stage IV according to the Cancer Staging Manual of the American Joint Committee on Cancer.

[0147] The compounds and salts thereof can be formulated as mentioned above as pharmaceutical compositions (e.g. liquids, suspensions, emulsions, lozenges, sachets, ampoules, aerosols, powders, granules, tablets, pills, capsules, injections, solutions etc.) comprising at least one such compound alone or optionally in a mixture with pharmaceutically acceptable carriers, excipients and/or diluents.

[0148] The compounds/salts thereof and pharmaceutical compositions may be formulated for intravenous or oral administration, e.g. by inhalation, for nasal administration or for administration by injection such as subcutaneous injection.

[0149] The following paragraphs are preferred embodiments of the invention:

1. A compound comprising:

[0150] a cyclic peptide comprising at least

(a) an amino acid X.sub.1 being selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y, further
(b) an amino acid sequence R-W-H, and further
(c) an amino acid X.sub.11 being selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y, or a peptidomimetic thereof, or

[0151] a cyclic peptide comprising at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein the amino acid X.sub.1 is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y, wherein the amino acids X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.11, X.sub.12, X.sub.13, and X.sub.14 are independently selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y, and wherein X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.12, X.sub.13, and X.sub.14 are optionally present in the amino acid sequence, or a peptidomimetic thereof.

2. The compound of paragraph 1, wherein the amino acid X.sub.1 is an amino acid having an NH.sub.2 group, such as K, R, N, or Q, and/or

[0152] wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids with negatively charged side chains such as E or D, or amino acids with non-polar side chains such as A, V, L or I, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids with an NH.sub.2 group such as K, R, N, or Q, and amino acids with non-polar side chains such as A, V, L or I, wherein X.sub.4 is optionally present and optionally selected from the group consisting of amino acids with non-polar or non-charged side changes and aromatic ring structures such as F, W, or Y, and amino acids with non-polar side chains such as A, V, L or I, wherein X.sub.5 is optionally present and optionally selected from the group consisting of amino acids with non-polar or non-charged side changes and aromatic rings structures such as F, W, or Y, and amino acids with non-polar side chains such as A, V, L or I, wherein X.sub.6 is optionally present and optionally selected from the group consisting of G and amino acids with non-polar side chains such as A, V, L or I, wherein X.sub.7 is optionally present and optionally selected from the group consisting of amino acids with an NH.sub.2 group such as K, R, N, or Q, and amino acids with non-polar side chains such as A, V, L or I, wherein X.sub.11 is selected from the group consisting of amino acids with negatively charged side chains such as E or D, and amino acids with non-polar side chains such as A, V, L or I, wherein X.sub.12 is optionally present and optionally selected from the group consisting of G and amino acids with non-polar side chains such as A, V, L or I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids with non-polar or non-charged side chains and aromatic rings structures such F, W, or Y, and amino acids with non-polar side chains such as A, V, L or I, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids with an NH.sub.2 group such as K, R, N, or Q, and amino acids with non-polar side chains such as A, V, L or I.

3. The compound of paragraph 1 or 2,

[0153] wherein X.sub.1 is selected from the group consisting of K, R, N, and Q, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is present and optionally E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q.

4. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably K, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is present and E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, or a peptidomimetic thereof.
5. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably K, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is present and E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, or a peptidomimetic thereof.
6. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably K, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, or a peptidomimetic thereof.
7. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably K, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is present and optionally E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, or a peptidomimetic thereof.
8. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably K, wherein X.sub.2 is optionally present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 present and is optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is present and optionally E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, or a peptidomimetic thereof.
9. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably K, wherein X.sub.2 is present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 is present and is optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is present and optionally E or D, wherein X.sub.12 is optionally present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, or a peptidomimetic thereof.
10. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably K, wherein X.sub.2 is present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is present and is optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4 is present and is optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6 is present and is optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is optionally E or D, wherein X.sub.12 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is optionally present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, or a peptidomimetic thereof.
11. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably K, wherein X.sub.2 is present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is present and is optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is present and optionally E or D, wherein X.sub.12 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is optionally present and optionally selected from the group consisting of amino acids K, R, N, and Q, or a peptidomimetic thereof.
12. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises at least the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7-R-W-H-X.sub.11-X.sub.12-X.sub.13-X.sub.14, wherein X.sub.1 is present and optionally selected from the group consisting of K, R, N, and Q, preferably K, wherein X.sub.2 is present and optionally selected from the group consisting of amino acids E and D, wherein X.sub.3 is present and is optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5 is present and optionally selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7 is present and optionally selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is present and optionally E or D, wherein X.sub.12 is present and optionally selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13 is present and optionally selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14 is present and is optionally selected from the group consisting of amino acids K, R, N, and Q, or a peptidomimetic thereof.
13. The compound of any one of the preceding paragraphs, wherein X.sub.1 is selected from the group consisting of K, R, N, and Q, preferably K, wherein X.sub.2, if present, is selected from the group consisting of amino acids E and D, wherein X.sub.3, if present, is selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.4, if present, is selected from the group consisting of amino acids F, W, and Y, wherein X.sub.5, if present, is selected from the group consisting of amino acids F, W, and Y, wherein X.sub.6, if present, is selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.7, if present, is selected from the group consisting of amino acids K, R, N, and Q, wherein X.sub.11 is D or E, wherein X.sub.12, if present, is selected from the group consisting of amino acids G, A, V, L and I, wherein X.sub.13, if present, is selected from the group consisting of amino acids F, W, and Y, and wherein X.sub.14, if present, is selected from the group consisting of amino acids K, R, N, and Q.
14. The compound of any one of the preceding paragraphs, wherein X.sub.1 is K, wherein X.sub.2, if present, is E, wherein X.sub.3, if present, is Q, wherein X.sub.4, if present, is W, wherein X.sub.5, if present, is F, wherein X.sub.6, if present, is G, wherein X.sub.7, if present, is N, wherein X.sub.11 is E, wherein X.sub.12, if present, is G, wherein X.sub.13, if present, is Y, and wherein X.sub.14, if present, is R.
15. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises, optionally consists of, the amino acid sequence K-R-W-H-E (SEQ ID No.: 34), K-N-R-W-H-E (SEQ ID No.: 35), K-G-N-R-W-H-E (SEQ ID No: 36), or a peptidomimetic thereof.
16. The compound of any one of the preceding paragraphs, wherein said peptide does not comprise the amino acid sequence N-R-W-H-E (SEQ ID No.: 2), the amino acid sequence K-R-W-H-E and a DOTA modification, the amino acid sequence K-G-N-R-W-H-E-G, the amino acid sequence K-E-Q-W-F-G-N-R-W-H-E-G-Y-R (SEQ ID No.: 6), or a peptidomimetic thereof.
17. The compound of any one of the preceding paragraphs, wherein the cyclic peptide or peptidomimetic thereof comprises a modification.
18. The compound of paragraph 17, wherein the modification comprises an amino acid, amino acid derivative, a lipophilic modification, or an aromatic hydrophobic modification, optionally the modification comprises phenyl acetic acid or 3-indole acetic acid.
19. The compound of paragraph 17 or 18, wherein the modification is not DOTA or a myristoyl group.
20. The compound of any one of the preceding paragraphs, comprising a chemical bond between two adjacent amino acids of the cyclic peptide which is not a chemical bond between the N-terminus of the a amino acid and the C-terminus of a second amino acid of the two adjacent amino acids.
21. The compound of paragraph 20, wherein the chemical bond between the two adjacent amino acids involves the amino acid side chain of at least one of said two adjacent amino acids.
22. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises a chemical bond selected from the group consisting of a chemical bond between an N-terminal amino group of an amino acid and an amino acid side chain, a chemical bond between a C-terminal carboxyl group of an amino acid and an amino acid side chain, and a chemical bond between an amino acid side chain of a first amino acid of the peptide and an amino acid side chain of a second amino acid of the peptide.
23. The compound of any one of the preceding paragraphs, wherein the cyclic peptide comprises a chemical bond selected from the group consisting of a chemical bond between an N-terminal amino group of an amino acid and a carboxyl group of an amino acid side chain, preferably of E or D, a chemical bond between a C-terminal carboxyl group of an amino acid and an amino group of an amino acid side chain, preferably of K, R, N or Q, and a chemical bond between an amino group of an amino acid side chain of a first amino acid of the peptide, preferably of K, R, N or Q, and a carboxyl group of an amino acid side chain of a second amino acid of the peptide, preferably of E or D.
24. The compound of any one of the preceding paragraphs, wherein the peptide has the amino acid sequence K-R-W-H-E (SEQ ID No.: 34), K-N-R-W-H-E (SEQ ID No.: 35) or K-G-N-R-W-H-E (SEQ ID NO.: 36), comprising a chemical bond selected from the group consisting of a chemical bond between an N-terminal amino group of an amino acid and an amino acid side chain, optionally a carboxyl group of an amino acid side chain, a chemical bond between a C-terminal carboxyl group of an amino acid and an amino acid side chain, optionally an amino group of an amino acid side chain, and a chemical bond between an amino acid side chain of a first amino acid of the peptide and an amino acid side chain of a second amino acid of the peptide, optionally between a carboxyl group of the amino acid side chain of the first amino acid and an amino group of the amino acid side chain of the second amino acid.
25. The compound of paragraph 23, wherein the peptide has the amino acid sequence K-R-W-H-E (SEQ ID No.: 34) and comprises a chemical bond between an N-terminal amino group of an amino acid and an amino acid side chain, preferably between an N-terminal amino group of an amino acid and a carboxyl group of an amino acid side chain, optionally of E.
26. The compound of any one of paragraphs 21 to 25, wherein the amino acid side chain is the amino acid side chain of an amino acid selected from the group consisting of the amino acids E, D, K, R, N and Q.
27. The compound of any one of paragraphs 20 to 26, wherein the chemical bond comprises the carboxyl group of an amino acid side chain of an amino acid E or D and/or wherein the chemical bond comprises the amino group of an amino acid side chain of any one of the amino acids K, R, N or Q.
28. The compound of any one of paragraphs 21 to 27, wherein the amino acid side chain is modified or truncated.
29. The compound of any one of the preceding paragraphs, wherein at least one amino acid of the cyclic peptide is a D-amino acid.
30. The compound of paragraph 29, wherein 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids are D-amino acids.
31. The compound of any one of the preceding paragraphs, wherein at least one amino acid of the amino acid sequence R-W-H is a D-amino acid.
32. The compound of any one of paragraph 31, wherein at least W is a D-amino acid.
33. The compound of any one of the preceding paragraphs, wherein W is a D-amino acid.
34. The compound of any one of the preceding paragraphs, wherein the peptide has the amino acid sequence K-R-W-H-E (SEQ ID No.: 34), K-N-R-W-H-E (SEQ ID No.: 35) or K-G-N-R-W-H-E (SEQ ID NO.: 36), comprising a chemical bond selected from the group consisting of a chemical bond between an N-terminal amino group of an amino acid and an amino acid side chain, optionally a carboxyl group of an amino acid side chain, a chemical bond between a C-terminal carboxyl group of an amino acid and an amino acid side chain, optionally an amino group of an amino acid side chain, and a chemical bond between an amino acid side chain of a first amino acid of the peptide and an amino acid side chain of a second amino acid of the peptide, optionally between a carboxyl group of the amino acid side chain of the first amino acid and an amino group of the amino acid side chain of the second amino acid, wherein at least one amino acid is a D-amino acid, preferably at least one amino acid of the amino acid sequence R-W-H is a D-amino acid.
35. The compound of any one of the preceding paragraphs, wherein the peptide has the amino acid sequence K-R-W-H-E (SEQ ID No.: 34) comprising a chemical bond between an N-terminal amino group of an amino acid and an amino acid side chain, preferably a carboxyl group of an amino acid side chain, more preferably between the N-terminal amino group of K and the carboxyl group of the amino acid side chain of E, wherein at least one amino acid is a D-amino acid, preferably at least one amino acid of the amino acid sequence R-W-H is a D-amino acid.
36. The compound of any one of the preceding paragraphs, wherein the peptide has the amino acid sequence K-R-W-H-E (SEQ ID No.: 34) comprising a chemical bond between the N-terminal amino group of K and the carboxyl group of the amino acid side chain of E, and wherein W is a D-amino acid.
37. A pharmaceutical composition comprising the compound of any one of the preceding paragraphs and a pharmaceutically acceptable carrier.
38. The compound of any one of paragraphs 1 to 36 or the pharmaceutical composition of paragraph 37, wherein the compound is formulated for intravenous, oral, nasal, or subcutaneous administration.
39. The compound of any one of paragraphs 1 to 36 or 38 or the pharmaceutical composition of paragraph 37 or 38 for use as a medicament.
40. The compound of any one of paragraphs 1 to 36, 38 or 39 or the pharmaceutical composition of any one of the preceding paragraphs 37 to 39 for use in treating a disease selected from the group consisting of cancer, an angiogenesis related disease, a disease from the field of ophthalmology, diseases associated with an increased invasive potential of cells, and inflammatory disorders in a human being.
41. The compound of paragraph 40 or the pharmaceutical composition of paragraph 40, wherein the cancer is a metastasizing cancer.
42. The compound of paragraph 40 or 41, or the pharmaceutical composition of paragraph 40 or 41, wherein the disease is selected from the group consisting of estrogen receptor-dependent breast cancer, estrogen receptor-independent breast cancer, hormone receptor-dependent prostate cancer, hormone receptor-independent prostate cancer, brain cancer, renal cancer, colon cancer, familial adenomatous polyposis (FAP), colorectal cancer, pancreatic cancer, bladder cancer, esophageal cancer, stomach cancer, genitourinary cancer, gastrointestinal cancer, uterine cancer, ovarian cancer, astrocytomas, gliomas, skin cancer, squamous cell carcinoma, Keratoakantoma, Bowen disease, cutaneous T-Cell Lymphoma, melanoma, basal cell carcinoma, actinic keratosis; ichtiosis; acne, acne vulgaris, sarcomas, Kaposi's sarcoma, osteosarcoma, head and neck cancer, small cell lung carcinoma, non-small cell lung carcinoma, leukemia, lymphomas and/or other blood cell cancers, thyroid resistance syndrome, diabetes, thalassemia, cirrhosis, protozoal infection, rheumatoid arthritis, rheumatoid spondylitis, all forms of rheumatism, osteoarthritis, gouty arthritis, multiple sclerosis, insulin dependent diabetes mellitus, non-insulin dependent diabetes, asthma, rhinitis, uveithis, lupus erythematoidis, ulcerative colitis, Morbus Crohn, inflammatory bowel disease, chronic diarrhea, psoriasis, atopic dermatitis, bone disease, fibroproliferative disorders, atherosclerosis, aplastic anemia, DiGeorge syndrome, Graves' disease, epilepsia, status epilepticus, alzheimer's disease, depression, schizophrenia, schizoaffective disorder, mania, stroke, mood-incongruent psychotic symptoms, bipolar disorder, affective disorders, meningitis, muscular dystrophy, multiple sclerosis, agitation, cardiac hypertrophy, heart failure, reperfusion injury, diabetic retinopathy, age-related macular degeneration, and obesity in a human being.
43. The compound of any one of paragraphs 40 to 42 or pharmaceutical composition for use of any one of paragraphs 40 to 42, wherein said cancer shows expression of CD44v6.
44. The compound of any one of paragraphs 40 to 43 or pharmaceutical composition for use of any one of paragraphs 40 to 43, wherein said cancer is classifiable as Stage III or Stage IV according to the TNM anatomic/prognostic group system of the cancer staging system of the American Joint Committee on Cancer.
45. The compound of any one of paragraphs 40 to 43 or pharmaceutical composition for use of any one of paragraphs 40 to 43, wherein said cancer is classifiable as Stage IV according to the TNM anatomic/prognostic group system of the cancer staging system of the American Joint Committee on Cancer.
46. The compound for use of any of paragraphs 40 to 45 or pharmaceutical composition for use of any of paragraphs 40 to 45, wherein said cancer is a metastasizing cancer selected from the group consisting of metastasizing forms of Hodgkin lymphoma, colorectal cancer, cervical cancer, lung cancer, skin cancer such as squamous cell cancer or basal cell carcinoma, head and neck cancer, gastric cancer, pancreatic cancer, head and neck squamous cell cancer, and breast cancer.
47. The compound for use of any of paragraphs 40 to 46 or pharmaceutical composition for use of any of paragraphs 40 to 46, wherein said cancer is a metastasizing cancer selected from the group consisting of metastasizing forms of Hodgkin lymphoma, colorectal cancer, cervical cancer, lung cancer, skin cancer such as squamous cell cancer or basal cell carcinoma, head and neck cancer, gastric cancer, pancreatic cancer, and breast cancer, wherein said metastasizing cancer is classifiable as Stage IV according to the TNM anatomic/prognostic group system of the cancer staging system of the American Joint Committee on Cancer, and wherein said metastasizing cancer shows expression of CD44v6.

[0154] The invention is now described with respect to experiments which, however, are not to be construed in a limiting sense.

EXAMPLES

Example 1—Synthesis Protocol of D3alga1 (Cf. FIGS. 1 and 9) by Solid Phase Cyclisation

[0155] Resin loading: 200 mg (ca. 320 μmol) 2-chlorotrityl chloride (Iris Biotech GmbH, Marktredwitz, Germany; Code BR-1060) in a filter equipped 5 mL-syringe are swelled with ca. 3 mL of dichloromethane for 10 min; excess solvent is removed before incubation with 40.9 mg (100 μmol) Fmoc-Glu(OAll)-OH and 70 μL (51.9 mg, 402 μmol) DIPEA in 2 mL dichloromethane for 90 min; then capping with 10% methanol, 5% DIPEA in dichloromethane for 2×10 min; final washing with each 2×DMF, dichloromethane & diethylether followed by (short) drying on vacuum line.

[0156] SPPS: resin is transferred to a reaction vessel (ABI 433A), using standard FastmocUV0.05 mmol-chemistry (solvent: NMP; amino acids: each 500 μmol weighed in cartridges; HBTU-activation; base: DIPEA; deprotection: 20% piperidinein NMP) building blocks used: Fmoc-Lys(Boc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-His(Trt)-OH (all obtained from Orpegen Peptide Chemicals GmbH, Heidelberg, Germany); 158 mg (300 μmol) Fmoc-D-Trp(Boc)-OH are activated with 110 mg (290 μmol) HATU, which are weighed in one amino acid cartridge, then standard amount DIPEA is added and coupling time is elongated by 15 min; final Fmoc-deprotection.

[0157] OAll-deprot.: product resin is transferred to a filter equipped 5 mL-syringe and swollen in dichloromethane; excess solvent is removed before incubation with ca. 5 mg (ca. 4 μmol) palladium-tetrakis(triphenylphosphine) and ca. 50 mg (ca. 850 μmol) dimethylamine borane in 2 mL dichloromethane for 25 min in the stoppered syringe; solution is removed, resin washed with dichloromethane and incubated 2×5 min with 3 mL of 5% 2-aminoethanol in dichloromethane in the stoppered syringe; washing with each 3× dichloromethane, NMP, methanol, dichloromethane and diethyl ether.

[0158] Cyclisation: (next day) the resin is swollen in dichloromethane and washed with NMP 3×3 mL; after removal of excess solvent 130 mg (250 μmol) PyAOP in 2 mL NMP are added; 5 min later 100 μL (74.2 mg, 574 μmol) DIPEA in 500 μL NMP are added and the whole reaction mixture is shaken for 30 min; resin is washed each 3×NMP, methanol, dichloromethane and diethyl ether before drying on vacuum line (300 mg product resin).

[0159] Deprotection: dried resin is directly treated with 5 mL of 2.5% water, 2.5% triisopropylsilane in TFA for 45 min; after filtration TFA is removed by coevaporation with 2×20 mL dichloromethane; raw peptide is precipitated and washed with diethylether, collected by centrifugation and dried in vacuo (ca. 70 mg).

[0160] Purification: raw peptide is taken up in 5 mL water and heated to 45° C. for 90 min before separation on a waters XBridge BEH130Prep C18 (5 μm, 19×150 mm) column; gradient: 8-20% acetonitrile/water (0.1% TFA) in 10 min flow: 20 mL/min; ambient temperature.

[0161] Yield: 21.65 mg (29.4 μmol; 29.4% based on resin loading) after lyophilisation.

[0162] Gradient: 0-66% acetonitrile/water (0.05% TFA) in 20 min; Thermo Scientific Hypersil gold (1.9 μm 200×2.1 mm), flow: 200 μL/min Temp: 60° C.

[0163] Correct product was confirmed by mass spectronomy.

Example 2—Synthesis Protocol of Alga1 (Cf. FIG. 1) by Solution Phase Cyclisation

[0164] Resin loading: 200 mg (ca. 320 μmol) 2-chlorotrityl chloride in a filter equipped 5 mL-syringe are swelled with ca. 3 mL of dichloromethane for 10 min; excess solvent is removed before incubation with 40.9 mg (100 μmol) Fmoc-Glu(OH)-OtBu and 70 μL (51.9 mg, 402 μmol) DIPEA in 2 mL dichloromethane for 90 min; then capping with 10% methanol and 5% DIPEA in dichloromethane for 2×10 min; final washing with each 2×NMP, dichloromethane and diethylether followed by (short) drying on the vacuum line.

[0165] SPPS: resin is transferred to a reaction vessel (ABI 433A), using standard FastmocUV0.05 mmol-chemistry (solvent: NMP; amino acids: each 500 μmol weighed in cartridges; HBTU-activation; base: DIPEA; deprotection: 20% piperidine) building blocks used: Fmoc-Lys(Boc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Trp(Boc)-OH, Fmoc-His(Trt)-OH (see Example 1); final Fmoc-deprotection.

[0166] Cleavage: product resin is transferred to a filter equipped 10 mL-syringe and swollen in dichloromethane; excess solvent is removed before incubation with 7.5 mL of 10% acetic acid and 20% trifluoroethanol in dichloromethane for 2×60 min in the stoppered syringe; trifluoroethanol and dichloromethane are removed in vacuo from the collected filtrates, acetic acid is removed by coevaporation with 2×30 mL toluene.

[0167] Cyclisation: the residue is taken up in 30 mL of DMF and 69.7 μL (50.6 mg, 500 μmol) triethylamine before 130 mg (250 μmol) PyAOP are added; reaction is carried out for 30 min after solution turns intense yellow (otherwise 250 μmol of additional triethylamine are added); reaction is quenched by addition of 50 μL of water; solvent and triethylamine are removed in high vacuo.

[0168] Deprotection: the residue of the DMF removal is directly treated with 5 mL of 2.5% water, 2.5% triisopropylsilane in TFA for 45 min; TFA is removed by 2× coevaporation with 20 mL dichloromethane; raw peptide is precipitated and washed with diethylether, collected by centrifugation and dried on the vacuum line. (ca. 100 mg).

[0169] Purification: raw peptide is taken up in 5 mL water and heated to 45° C. for 90 min before separation on a waters XBridge BEH130Prep C18 (5 μm, 19×150 mm) column; gradient: 8-20% acetonitrile/water (0.1% TFA) in 10 min.

[0170] Yield: 42.84 mg (58.1 μmol; 58.1% based on resin loading) after lyophilisation.

[0171] The control peptide in the following Examples is N-A-A-A-E.

Example 3—A Cyclic CD44v6 5mer (alga1, cf. FIG. 1) and a cyclic CD44v6 5Mer Containing a D-Amino Acid at Position 3 (D3alga1, Cf. FIGS. 1 and 9) Block Activation of c-Met and Erk (Cf. FIG. 3)

[0172] Human adenocarcinoma cells, Panc1, were seeded at 2×10.sup.5 cells per well in a 6-well plate. The day after seeding the cells, they were starved for 24 h. The following day, the cells were treated as indicated with either alga1 or D3alga1, a control peptide (N-A-A-A-E) at a concentration of 30 nM for 5 min at 37° C. prior to induction with HGF (10 ng/ml) at 37° C. for 5 min. Results are given in FIG. 3 (A: alga1; B: D3alga1).

Example 4—Cyclic CD44v6 5Mers Containing a D-Amino Acid at Positions 1, 2 or 3, Respectively (D-Amino Acid at Position 1: D1alga1, at Position 2: D2alga1, at Position 3: D3alga1) Blocks Activation of c-Met and Erk (FIG. 4)

[0173] Human adenocarcinoma cells, Panc1, were seeded at 2×10.sup.5 cells per well in a 6-well plate. The day after seeding, the cells were starved for 24 h. The following day, the cells were treated as indicated with either D1alga1, D2alga1 or D3alga1, a human CD44v6 14mer (h14mer) or control peptide (N-A-A-A-E) at a concentration of 30 nM for 5 min at 37° C. prior to induction with HGF (10 ng/ml) at 37° C. for 5 min. Results are given in FIG. 4.

Example 5—Wound Healing Assay (Cf. FIG. 5)

[0174] A wound healing assay is used to demonstrate the blocking capacity of the tested reagents in respect of migration of cells. Cell migration is connected to angiogenesis where cells need to migrate in order to form new blood vessels. Hence, if a reagent blocks cell migration in a wound healing assay, this also strongly indicates the reagent's ability to prevent angiogenesis. FIG. 5A: Panc 1 cells were seeded in 12-well plates at a concentration of 2.5×10.sup.5 cells per well. After 24 hours, the cells form a confluent monolayer in which a scratch is inserted using a sterile pipette tip. Medium was aspirated to remove scratched cells and replaced by new growth medium containing reagents as indicated (v6 14mer, D1alga1, D2alga1 or D3alga1) at a concentration of 30 nM tested for their blocking quality. After an incubation time of 10 min at 37° C., growth factor HGF was added to induce migration (HGF 20 ng/ml). Photos of the cells were taken 24 hours after induction using a Canon Power Shot S620 digital camera. FIG. 5B: The computer program ImageJ was used for quantitative evaluation. An area in the wound was defined and the cell invaded area was measured. The efficiency of wound closure is represented as percentage of invasion into the scratch. In particular, D3alga1 blocks cell migration most efficiently.

Example 6—Side by Side Comparison of the Human CD44v6 14Mer (V6 14MER), Algal and D3alga1 for their Effect on Tumor Growth Inhibition and Inhibition on Tumor Metastasis (FIG. 6)

[0175] To evaluate the inhibition of tumor growth, L3.6 pl cells were orthotopically implanted into nude mice. The treatment of all animals started one week after tumor growth. The groups consisted of 8 animals, the PBS group of 6 animals. This inhibition experiment shows that the primary tumor was drastically inhibited in with a dose of 20 μg 3× weekly (cf. FIG. 6A). The reduction of the application frequency to once weekly 60 μg resulted as well in reduction of the tumor growth. All treatments were successful and significant compared to the control group (PBS 3× weekly). To evaluate the inhibition of metastatic spreading to the liver, the groups consisted of 8 animals, the PBS group of 6 animals. With an application of 3× weekly, no macroscopic metastases were observed. Application once weekly with all compounds resulted in tumor metastasis to the liver with the ranking V6 14MER<D3alga1<alga1, and the number of metastases per animal was lower compared to the control group. “ctrl pep”=control peptide N-A-A-A-E

Example 7—Side by Side Comparison of the Human CD44v6 14Mer (V6 14MER), Algal and D3alga 1 for their Effect on Regression of Already Established Metastases (FIG. 7)

[0176] L3.6pl cells were orthotopically implanted into nude mice. In contrast to Example 6 (FIG. 6), the treatment was started 3 weeks after tumor implantation; at this time all animals showed liver metastases. FIG. 7A shows inhibition of the tumor growth. The groups consisted of 8 animals, the PBS group of 6 animals. This inhibition experiment shows that the primary tumor was drastically inhibited in with a dose of 20 μg 3× weekly. The reduction of the application frequency to once weekly 60 μg resulted in reduction of the tumor growth as well. All treatments were successful and significant compared to the control group (PBS 3× weekly).

[0177] FIG. 7B depicts regression of established liver metastases. The groups consisted of 8 animals, the PBS group of 6 animals. With an application 3× weekly, no macroscopic metastases could be detected. Application once weekly with all compounds resulted in a regression of metastases with the ranking V6 14MER<D3alga1<alga1, and the number of metastases per animal was lower compared to the PBS control group. “ctrl pep”=control peptide N-A-A-A-E

Example 8—Comparison of the Tumor Accumulation of the 14-Mer Linear Peptide and Algal and D3alga1 after Labelling with .SUP.68.Ga Using PET Imaging

[0178] L3.6pl cells were subcutaneously implanted into nude mice. Animals were treated using .sup.68Ga labeled forms of the 14-mer linear peptide (V6 14MER), alga1, and D3alga and PET imaging was performed 4 h after treatment. Given a similar accumulation in the kidney (FIG. 8 images on the left), it can be shown, that the tumor accumulation of the substances is increasing with the order v6 14mer<alga1<D3alga1.

Example 9—Wound Healing Assay (Cf. FIG. 15)

[0179] A wound healing assay is used to demonstrate the blocking capacity of the indicated reagents in respect of migration of cells. Cell migration is connected to angiogenesis where cells need to migrate in order to form new blood vessels. Angiogenesis is related to cancer metastasis. Hence, if a reagent blocks cell migration in a wound healing assay, this also strongly indicates the reagent's ability to prevent angiogenesis. Panc 1 cells were seeded in 6-well plates at a concentration of 3×10.sup.5 cells per well and were allowed to adhere and form a confluent monolayer. After a starving period of 24 hours, a scratch was inserted using a sterile pipette tip. Medium was aspirated to remove scratched cells and replaced by new starving medium containing reagents as indicated at a concentration of 30 nM tested for their blocking quality.

[0180] The following reagents were added to the medium at a concentration of 500 nM to test their blocking efficiency: D3-epga1, D4-epga1, D2-epal1, D3-epal1, D4-epal1, D3-alga1, D3-alga2, D4-alga2, D5-alga2, D6-alga3, Epga-1, Epal-1, Alga-2 and Alga-3. After 30 min incubation at 37° C., growth factor HGF was added to induce migration (HGF 100 ng/ml). Photos of the cells were taken immediately after scratch (Day 1), 24 hours (Day 2) and 48 hours (D3) after induction using a Canon Power Shot G12 digital camera. As can be taken from the photo series, all tested peptides are efficient in blocking cell migration. Most efficient blocking of cell migration was observed for D2-epal1, D3-alga1, D6-alga3 and Alga-2.

Example 10—Clinical Study

[0181] Monotherapy with intravenous infusion of D2-epal1, D3-alga1, D6-alga3 and Alga-2 (cf. FIGS. 9-12) is performed. In a first step, this includes a Phase I dose escalation study on tolerability, safety and pharmacokinetics in patients with various end stage epithelial cancer types and correlative studies on CD44v6 expression. Further, the expansion cohort for preliminary efficacy in selected epithelial cancer types is tested for the aforementioned cyclic peptides. Subsequently, a multi-center (n=2-4) European study is performed.