The present invention relates to the discovery of a method for identifying a treatment regimen for a patient diagnosed with cancer, predicting patient resistance to therapeutic agents and identifying new therapeutic agents, obtaining the specificity profile of a therapeutic agent, a method of designing a scaffold of a therapeutic agent directed against a drug-resistant target, drug scaffolds, and methods of uses thereof to identify drugs to treat diseases such as cancer. Specifically, the present invention relates to the use of an algorithm to identify a mutation in a kinase, determine if the mutation is an activation or resistance mutation and then to suggest an appropriate therapeutic regimen. The invention also relates to the use of a pattern matching algorithm and a crystal structure library to predict the functionality of a gene mutation, predict the specificity of small molecule kinase inhibitors and for the identification of new therapeutic agents.

The present invention provides a crystal structure of human BTK with space group space group p 2 21 21 and has unit cell parameters a=38.155±2Å; b=72.394±2Å; c=103.946±2Å; a=90°; b=90°; g=90°; the BTK protein is complexed with N-((1R,2S)-2-Acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.

The present invention relates to a polypeptide binding to human serum albumin and comprising or consisting of an amino acid sequence selected from the group consisting of: (a) GVTLFVALYDY(X.sup.1)(X.sup.2)(X.sup.3)(X.sup.4)(X.sup.5) (X.sup.6)D(X.sup.7)SFHKGEKFQIL(X.sup.8)(X.sup.9)(X.sup.10)(X.sup.11)(X.sup.12)G(X.sup.13)(X.sup.14)W(X.sup.15)(X.sup.16)RSLTTG(X.sup.17)(X.sup.18)G(X.sup.19)IPSNYVAPVDSIQ (SEQ ID NO: 1), wherein (X.sup.1) is A, V, I, L, M, G, P, S, T, N, Q, C, R, H, K, D or E; (X.sup.2) is R, H, K, A, V, I, L, M, G, P, S, T, N, Q or C; (X.sup.3) is R, H, K, S, T, N, Q, C, F, Y, W, A, V, I, L, M, G or P; (X.sup.4) is S, T, N, Q, C, A, V, I, L, M, G, P, R, H, K, F, Y, W, D or E; (X.sup.5) is S, T, N, Q, C, D, E, F, Y, W, A, V, I, L, M, G, P, R, H or K; (X.sup.6) is F, Y, W, A, V, I, L, M, G, P, R, H, K, S, T, N, Q or C; (X.sup.7) is A, V, I, L, M, G, P, R, H or K; (X.sup.8) is S, T, N, Q, C, D or E; (X.sup.9) is S, T, N, Q, C, D, E, A, V, I, L, M, G, P, F, Y or W; (X.sup.10) is A, V, I, L, M, G or P; (X.sup.11) is F, Y, W, R, H or K; (X.sup.12) is S, T, N, Q, C, F, Y or W; (X.sup.13) is F, Y, W, R, H, K, S, T, N, Q, C, D, E, A, V, I, L, M, G or P; (X.sup.14) is F, Y, W, A, V, I, L, M, G or P; (X.sup.15) is D, E, A, V, I, L, M, G or P; (X.sup.16) is A, V, I, L, M, G or P; (X.sup.17) is D, E, A, V, I, L, M, G, P, R, H or K; (X.sup.18) is S, T, N, Q, C, A, V, I, L, M, G or P; (X.sup.19) is F, Y, W, S, T, N, Q or C; and (b) an amino acid sequence which is at least 90% identical to the amino acid sequence of (a), wherein the identity determination excludes amino acid positions (X.sup.1) to (X.sup.19).

The present invention provides an anti-influenza virus agent that targets biomolecules of host cells including human cells and a method of screening a candidate molecule for the anti-influenza virus agent. That is, the present invention is an anti-influenza virus agent that has an effect of suppressing expression or a function of a gene that encodes a protein having an effect of suppressing incorporation of an influenza virus vRNA or an NP protein into influenza virus-like particles in host cells and the gene is at least one selected from the group including JAK1 gene and the like.

Hypoxia induced mitogenic factor (HIMF) is a member of the “found in inflammatory zone” (FIZZ)/resistin family of proteins and has potent mitogenic, angiogenic, and vasoconstrictive effects in the lung vasculature. The receptor/binding partners for this family of proteins have been largely unknown. We identified Bruton's tyrosine kinase (BTK) as a functional HIMF binding partner through GST-HIMF pull-downs and mass spectrometry. Using primary cultured HIMF-stimulated murine bone marrow cells, we demonstrated that BTK was recruited to the leading edge of the cells. We also demonstrated that BTK and the closely related tyrosine kinase Fyn, colocalized at the growth cone process in these cells. HIMF stimulation induced BTK autophosphorylation, which peaked at 2.5 minutes. A transwell migration assay showed that treatment with recombinant murine HIMF induced migration of primary cultured bone marrow cells, which was completely blocked by the BTK inhibitor, LFM-A13. In vivo studies, using the rat hindlimb ischemia model, revealed that HIMF can stimulate angiogenesis in the hypoxic tissue probably through inducing the migration of endothelial progenitor cells (EPCs) to areas of active angiogenesis. Our results indicate that HIMF may acts as a chemotactic molecule in stimulating the migration of leukocytes/EPCs from bone marrow to targeted tissues through activation of the BTK pathway.

Methods and compositions are described herein that inhibit FAK/ATK interactions. Such methods and compositions are useful for inhibiting cell adhesion and cancer metastasis.

Provided are methods for the identification of mutant kinases that are resistant to inhibition by a kinase inhibitor. In some embodiments, the methods may be used to assess a test compound or kinase inhibitor for the risk of the development of resistance in vivo, e.g., during clinical administration to treat a disease such as a cancer.

Chimeric polypeptides including (a) an extracellular targeting domain; (b) a transmembrane domain; (c) an intracellular linker for activation of T cells (LAT) domain or SLP-76 domain; and (d) an intracellular ZAP70 domain, wherein (a)-(d) are in N-terminal to C-terminal order are provided. Chimeric polypeptides including (a) an extracellular targeting domain; (b) a transmembrane domain; and (c) a ZAP70 domain, wherein (a)-(c) are in N-terminal to C-terminal order are also provided. In some embodiments, the chimeric polypeptide further includes a hinge domain, a signal sequence domain, and/or an intracellular signaling domain. Nucleic acid molecules encoding the chimeric polypeptides and expression vectors including the nucleic acids are also provided. Isolated cells (such as T cells or natural killer cells) expressing the chimeric polypeptides and methods of treating a subject with cancer with the isolated cells are provided.

In certain embodiments methods of treating X-Linked agammaglobulinemia (XLA) in a mammal are provided where the methods comprise: i) providing differentiated T cells and/or stem/progenitor cells from the mammal; ii) performing a targeted insertion of a corrective BTK cDNA at the BTK gene locus in said cells to provide a corrected BTK gene in said cells; and iii) introducing said cells into said mammal where said corrected BTK gene is expressed in a physiologically regulated manner.

The present invention relates to a polypeptide binding to fibroblast growth factor receptor 3 isoforms 3b and 3c (FGFR3b and FGFR3c), wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: (a) GVTLFVALYDYEVYGPTPMLSFHKGEKFQIL(X.sup.1)(X.sup.2)(X.sup.3) (X.sup.4)GPYWEARSL(X.sup.5)TGETG(X.sup.6)IPSNYVAPVDSIQ (SEQ ID NO: 1), wherein amino acid positions (X1) to (X.sup.6) may be any amino acid sequence; (b) an amino acid sequence which is at least 95% identical to the amino acid sequence of (a), wherein the identity determination excludes amino acid positions (X.sup.1) to (X.sup.6) and provided that the amino acid sequence EVYGPTPM (SEQ ID NO: 2) in amino acid positions 12 to 19 of SEQ ID NO: 1 is conserved and the amino acids P and Y in amino acid positions 37 and 38 of SEQ ID NO: 1 are conserved; (c) GVTLFVALYDYEVMSTTALSFHKGEKF QILSQSPHGQYWEARSLTTGETG(X.sup.6)IPSNYVAPVDSIQ (SEQ ID NO: 19), wherein the amino acid position (X.sup.6) may be any amino acid; and (d) an amino acid sequence which is at least 95% identical to the amino acid sequence of (c), wherein the identity determination excludes amino acid position (X.sup.6) and provided that the amino acid sequences EVMSTTA (SEQ ID NO: 20) in amino acid positions 12 to 18 of SEQ ID NO: 19 and SQSPH (SEQ ID NO: 21) in amino acid positions 31 to 35 of SEQ ID NO: 19 are conserved and the amino acids Q and Yin amino acid positions 37 and 38 of SEQ ID NO: 19 are conserved.