COMPOSITIONS AND METHODS FOR INHIBITING BLOOD CANCER CELL GROWTH

Abstract

Methods, compositions and uses for inhibiting the growth in blood cancer cells in a patient with one or more of a caffeic acid phenpropyl ester (GL8) analogue selected from the group consisting of As26, J229, J91, LL27, LL23, HM7, As25, MT26, and J205. The blood cancer cells can be myeloma, lymphoma and leukemia cells. The methods, compositions and uses can be in conjunction with the use of an IMiD to treat a patient. The compositions can include a pharmaceutically acceptable carrier, adjuvant or vehicle, a pharmaceutically acceptable salt or dietary supplement.

Claims

1. A method for inhibiting the growth of blood cancer cells comprising: contacting the cells with a caffeic acid phenpropyl ester (GL8) analogue selected from the group consisting of As26, J229, J91, LL27, LL23, As25, MT26, and J205, having the structures: ##STR00021## where, TABLE-US-00006 As26: R.sub.2 = R.sub.3 = R.sub.5 = H, R.sub.1 = R.sub.4 = OH, A = CO, X = O, R = (CH.sub.2).sub.3 Ph J229: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CH.sub.2, X = O, R = (CH.sub.2).sub.3 Ph J91: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = CH.sub.2CCPh LL27: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = (CH.sub.2).sub.5 Ph LL23: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = (CH.sub.2).sub.4 Ph As25: R.sub.3 = R.sub.4 = R.sub.5 = H, R.sub.1 = R.sub.2 = OH, A = CO, X = O, R = (CH.sub.2).sub.3 Ph MT26: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = CH.sub.2CH.sub.2 Ph(4-F) J205: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = CH.sub.2, R = (CH.sub.2).sub.2 Ph in an amount effective to inhibit the growth.

2. The method of claim 1, wherein the blood cancer cells are myeloma cells.

3. The method of claim 1, wherein the myeloma cells are immunomodulatory drug (IMiD) resistant.

4. The method of claim 1, wherein the myeloma cells are lenalidomide resistant.

5. The method of claim 1, wherein the blood cancer cells are lymphoma cells.

6. The method of claim 5, wherein the lymphoma cells are diffused large B-cell Lymphoma.

7. The method of claim 5, wherein the lymphoma cells are lenalidomide resistant.

8. The method of claim 5, wherein the lymphoma cells are immunomodulatory drug resistant.

9. The method of claim 1, wherein the blood cancer cells are leukemia cells.

10. A method for inhibiting the growth of blood cancer cells in a patient comprising: administering to a patient a therapeutically effective amount of a caffeic acid phenpropyl ester (GL8) analogue selected from the group consisting of As26, J229, J91, LL27, LL23, As25, MT26, and J205, having the structures: ##STR00022## where, TABLE-US-00007 As26: R.sub.2 = R.sub.3 = R.sub.5 = H, R.sub.1 = R.sub.4 = OH, A = CO, X = O, R = (CH.sub.2).sub.3 Ph J229: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CH.sub.2, X = O, R = (CH.sub.2).sub.3 Ph J91: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = CH.sub.2CCPh LL27: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = (CH.sub.2).sub.5 Ph LL23: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = (CH.sub.2).sub.4 Ph As25: R.sub.3 = R.sub.4 = R.sub.5 = H, R.sub.1 = R.sub.2 = OH, A = CO, X = O, R = (CH.sub.2).sub.3 Ph MT26: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = CH.sub.2CH.sub.2 Ph(4-F) J205: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = CH.sub.2, R = (CH.sub.2).sub.2 Ph.

11. The method of claim 10, wherein the blood cancer cells are myeloma cells.

12. The method of claim 10, wherein the myeloma cells are immunomodulatory drug (IMiD) resistant.

13. The method of claim 10, wherein the myeloma cells are lenalidomide-resistant.

14. The method of claim 10, wherein the blood cancer cells are lymphoma cells

15. The method of claim 14, wherein the lymphoma cells are diffused large B-cell Lymphoma.

16. The method of claim 14, wherein the lymphoma cells are lenalidomide resistant.

17. The method of claim 14, wherein the lymphoma cells are immunomodulatory drug resistant.

18. The method of claim 10, wherein the blood cancer cells are leukemia cells.

19. A composition for inhibiting the growth of blood cancer cells comprising: a therapeutically effective amount of a caffeic acid phenpropyl ester (GL8) analogue selected from the group consisting of As26, J229, J91, LL27, LL23, As25, MT26, and J205, having the structures: ##STR00023## where, TABLE-US-00008 As26: R.sub.2 = R.sub.3 = R.sub.5 = H, R.sub.1 = R.sub.4 = OH, A = CO, X = O, R = (CH.sub.2).sub.3 Ph J229: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CH.sub.2, X = O, R = (CH.sub.2).sub.3 Ph J91: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = CH.sub.2CCPh LL27: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = (CH.sub.2).sub.5 Ph LL23: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = (CH.sub.2).sub.4 Ph As25: R.sub.3 = R.sub.4 = R.sub.5 = H, R.sub.1 = R.sub.2 = OH, A = CO, X = O, R = (CH.sub.2).sub.3 Ph MT26: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = O, R = CH.sub.2CH.sub.2 Ph(4-F) J205: R.sub.1 = R.sub.4 = R.sub.5 = H, R.sub.2 = R.sub.3 = OH, A = CO, X = CH.sub.2, R = (CH.sub.2).sub.2 Ph.

20. The composition of claim 19, wherein the blood cancer cells are myeloma cells.

21. The composition of claim 19, wherein the myeloma cells are immunomodulatory drug (IMiD) resistant.

22. The composition of claim 19, wherein the myeloma cells are lenalidomide resistant.

23. The composition of claim 19, wherein the blood cancer cells are lymphoma cells.

24. The composition of claim 23, wherein the lymphoma cells are diffused large B-cell Lymphoma.

25. The composition of claim 19, wherein the blood cancer cells are leukemia cells.

26. The composition of claim 19, wherein the composition is a pharmaceutical composition.

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48. The method of claim 10, wherein the caffeic acid phenpropyl ester (GL8) analogue is As26 having the structure: ##STR00024## where R.sub.2═R.sub.3═R.sub.5═H,R.sub.1═R.sub.4═OH,A=CO,X═O,R═(CH.sub.2).sub.3Ph.

49. The method of claim 10, wherein the caffeic acid phenpropyl ester (GL8) analogue is J229 having the structure: ##STR00025## where R.sub.1═R.sub.4═R.sub.5═H,R.sub.2═R.sub.3═OH,A=CH.sub.2,X═O,R═(CH.sub.2).sub.3Ph.

50. The method of claim 48, wherein the administered therapeutically effective amount decreases a cereblon pathway gene or protein in the patient.

51. The method of claim 49, wherein the administered therapeutically effective amount decreases a cereblon pathway gene or protein in the patient.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] For the purpose of illustrating the invention, the drawings show aspects of one or more embodiments of the invention. However, it should be understood that the present invention is not limited to the precise arrangements and instrumentalities shown in the drawings, wherein:

[0023] FIG. 1 is a bar graph depicting cell growth inhibitory effect of caffeic acid phenpropyl ester (GL8) analogues according to certain aspects of the present disclosure at 10 uM concentration on IMiD-resistant human myeloma cells (KMM1);

[0024] FIG. 2 is a bar graph depicting cell growth inhibitory effect of caffeic acid phenpropyl ester (GL8) analogues at 1 uM concentration according to certain aspects of the present disclosure on human lymphoma cells (IMiD-resistant cell line—OCI-Ly3);

[0025] FIG. 3 is a bar graph depicting cell growth inhibitory effect of caffeic acid phenpropyl ester (GL8) analogues at 10 uM concentration according to certain aspects of the present disclosure on human lymphoma cells (IMiD-resistant cell line—OCI-Ly3);

[0026] FIG. 4 is a bar graph depicting cell growth inhibitory effect of caffeic acid phenpropyl ester (GL8) analogues at 10 uM concentration according to certain aspects of the present disclosure on human leukemia cells;

[0027] FIG. 5A is a graph showing the inhibition of myeloma cell lines treated with various concentrations of lenalidomide;

[0028] FIG. 5B is a graph showing the inhibition of myeloma cell lines treated with various concentrations of pomalidomide;

[0029] FIG. 5C is a table of ICso values of CAPE, GL8, As26 and J229 tested on both IMiD-sensitive (MMIR) and IMID-resistant human myeloma cells (KMM1 and JJN3);

[0030] FIG. 5D is a graph showing the inhibition of KMM1 cells (lenalidomide-resistant) treated with various concentrations of CAPE, GL8, As26 and J229;. 5E is a graph showing the inhibition of MM1R cells (lenalidomide-sensitive) treated with various concentrations of CAPE, GL8, As26 and J229;

[0031] FIG. 5F is a graph showing the inhibition of JJN3 cells (lenalidomide-resistant) treated with various concentrations of CAPE, GL8, As26 and J229;

[0032] FIG. 6 is a graph showing the apoptotic effect on KMM1 myeloma cells treated with veh/vehicle (DMSO), lenalidomide, pomalidomide, CAPE, GL8, As26 and J229;

[0033] FIG. 7A is a graph showing lymphoma cell growth inhibitory effect in comparison to a 3-day treatment of IMiDs;

[0034] FIG. 7B is a graph showing lymphoma cell growth inhibitory effect in comparison to 5-day treatment of IMiDs;

[0035] FIG. 7C is a graph showing lymphoma cell growth inhibitory effect in comparison to a 2-day treatment with GL8, As25, J229, HM7, and LL23.

[0036] FIG. 8 is an immunoblot showing the protein expression of IRF4 in human cell lines and myeloma patient samples; and

[0037] FIG. 9 is an immunoblot showing the effect of lenalidomide (IMiD), CAPE, GL8, As26, and J229 on human myeloma cell line MM1R.

DETAILED DESCRIPTION

[0038] In certain embodiments of the present invention, a systematic molecules design strategy was used to obtain 18 analogues of GL8/caffeic acid phenpropyl ester, which are set out in Table 1.

TABLE-US-00001 TABLE 1 Molecule Code (Used in Anti- blood Cancer Bioactivity Evaluation Experiments) Molecule Chemical Name 18A LL23 [00002] (E)-4-phenylbutyl 3-(3,4- dihydroxyphenyl)acrylate 17A LL27 [00003] (E)-4-phenylbutyl 3-(3,4- dihydroxyphenyl)acrylate 16A LL28 [00004] (E)-3-(3,4- dihydroxypheny1)-N-(3- phenylpropyl)acrylamide 15B HM5 [00005] (E)-phenethyl 3-(4- hydroxy-3,5- dimethoxyphenyl)acrylate 14A HM7 [00006] (E)-3-phenylpropyl 3-(4- hydroxy-3,5- dimethoxyphenyl)acrylate 13B MT49 [00007] (E)-phenethyl 3-(4- hydroxy-3- methoxyphenyl)acrylate 12B MT50 [00008] (E)-3-phenylpropyl 3-(4- hydroxy-3- methoxyphenyl)acrylate 11A LL14 [00009] (2E)-cinnamyl 3-(3,4- dihydroxyphenyl)acrylate 10A J91 [00010] (E)-3-phenylprop-2-ynyl 3-(3,4- dihydroxyphenyl)acrylate 9A J229 [00011] 4-((E)-3-(3- phenylpropoxy)prop-1- enyl)benzene-1,2-diol 8B J205 [00012] (E)-1-(3,4- dihydroxyphenyl)-6- phenylhex-1-en-3-one 7A As25 [00013] (E)-3-phenylpropyl 3- (2,3- dihydroxyphenyl)acrylate 6A As26 [00014] (E)-3-phenylpropyl 3- (2,5- dihydroxyphenyl)acrylate 5A MT72 [00015] (E)-3-phenylpropyl 3- (2,4- dihydroxyphenyl)acrylate 4A GL7 [00016] (E)-benzyl 3-(3,4- dihydroxyphenyl)acrylate 3A GL9 [00017] (E)-phenyl 3-(3,4- dihydroxyphenyl)acrylate 2A MT25 [00018] (E)-(4-methylphenethyl) 3-(3,4- dihydroxyphenyl)acrylate IA MT26 [00019] (E)-(4-fluorophenethyl) 3-(3,4- dihydroxyphenyl)acrylate

[0039] In certain embodiments of the present invention, the molecule design strategy used to obtain the 18 analogues of Table 1 is set out in Scheme 1.

##STR00020##

[0040] In certain embodiments of the present invention, a bioactivity evaluation was then carried out to evaluate the anti-blood cancer activity of the 18 analogues in Table 1 in comparison to the standard drug, lenalidomide, parent compounds CAPE, GL8 and propolis. In certain embodiments of the present invention, the bioactivity of the 18 analogs of Table 1 in human myeloma, lymphoma and leukemia cell lines was evaluated and analogues with superior anti-myeloma, anti-lymphoma and anti-leukemia activity were identified.

[0041] In certain embodiments of the present invention, the remarkable cancer cell growth inhibitory potential of caffeic acid phenpropyl ester analogues was established by treating human leukemia, myeloma and lymphoma cell lines with the analogues of Table 1 and measuring the viability of blood cancer cells by cell viability assay. The efficacy of the analogues of Table 1 in comparison to a standard chemotherapy drug was confirmed.

[0042] With reference to Table 1, Table 2 and FIG. 1, FIG. 1 is a bar graph depicting cell growth inhibitory effect of caffeic acid phenpropyl ester (GL8) analogues at 10 uM concentration according to certain aspects of the present disclosure on human myeloma cells (Cell line: KMM-1; 48 hr treatment). Caffeic acid phenpropyl ester (GL8) analogues that exhibit superior anti-myeloma cell growth inhibition, in decreasing order of bioactivity at 10 uM concentration, are As26, J229, J91, LL27, LL23 and HM7.

TABLE-US-00002 TABLE 2 Molecule Code/ Growth Bioactivity Assay Inhibition Treatment Condition Molecule (%) Len Lenalidomide 7.5 CAPE CAPE 14.7 GL8 GL8 28.2  1A MT26 25.9  2A MT25 21.6  3A GL9 26  4A GL7 15.9  5A MT72 −0.2  6A As26 89.7  7A As25 15.1  8B J205 22.2  9A J229 49.4 10A J91 31.7 11A LL14 16.1 12B MT50 13.6 13B MT49 6.5 14A HM7 26.6 15B HMS −8.6 16A LL28 15.8 17A LL27 30.5 18A LL23 27.2 19P Propolis −5.2

[0043] With reference to Table 3 and FIG. 2, FIG. 2 is a bar graph depicting cell growth inhibitory effect of caffeic acid phenpropyl ester (GL8) analogues according to certain aspects of the present disclosure at 1 uM concentration on human lymphoma cells (Cell line: OCI-LY3; 48 hr treatment).

TABLE-US-00003 TABLE 3 Molecule Code/ Bioactivity Assay Growth Treatment Inhibition Condition Molecule (%)  1A MT26 0.7  2A MT25 10.0  3A GL9 26.3  4A GL7 10.5  5A MT72 3.3  6A As26 26.6  7A As25 69.0  8B J205 18.7  9A J229 2.3 10A J91 0.3 11A LL14 −1 12B MTSO −0.7 13B MT49 −1.0 14A HM7 −4.9 15B HMS 3.1 16A LL28 −9.5 17A LL27 1.6 18A LL23 −9.3 19P Propolis 20.7 CAPE CAPE −24.3 GL8 GL8 −4.6

[0044] With reference to Table 1, Table 4 and FIG. 3, FIG. 3 is a bar graph depicting cell growth inhibitory effect of caffeic acid phenpropyl ester (GL8) analogues according to certain aspects of the present disclosure at 10 uM concentration on human lymphoma cells (Cell line: OCI-LY3; 48 hr treatment). Caffeic acid phenpropyl ester analogues according to certain aspects of the present disclosure that exhibited superior anti-lymphoma cell growth inhibition, in decreasing order of bioactivity at 10 uM concentration, are As26, HM7, As25, MT26 and J229.

TABLE-US-00004 TABLE 4 Growth Molecule Code/ Bioactivity Inhibition Assay Treatment Condition Molecule (%) CAPE CAPE 51.8 GL8 GL8 78.7 Len Lenalidomide 7.5  1A MT26 79.3  2A MT25 59.8  3A GL9 44.7  4A GL7 18.9  5A MT72 −4.5  6A As26 90.3  7A As25 84.0  8B J205 76.6  9A J229 78.2 10A J91 39.8 11A LL14 61.5 12B MT50 1.5 13B MT49 1.2 14A HM7 90.0 15B HMS −15.4 16A LL28 36.0 17A LL27 77.4 18A LL23 71.7 19P Propolis 3.1

[0045] With reference to Table 5 and FIG. 4, FIG. 4 is a bar graph depicting cell growth inhibitory effect of caffeic acid phenpropyl ester (GL8) analogues at 10 uM concentration according to certain aspects of the present disclosure on human leukemia cells (Cell line: HL-60; 48 hr treatment).

TABLE-US-00005 TABLE 5 Molecule Code/ Bioactivity Assay Treatment Growth Inhibition Condition Molecule (%) Len Lenalidomide 1.6 CAPE CAPE −6.8 GL8 GL8 36.0  1A M126 32.1  2A M125 28.7  3A GL9 6.8  4A GL7 20.5  5A M172 −8.2  6A As26 54.4  7A As25 13.6  8B J205 60.7  9A J229 54.3 10A J91 32.4 11A 1114 21.6 12B MT50 13.4 13B M149 14.4 14A HM7 24.1 15B HMS −13.3 16A 1128 8.7 17A 1127 35.2 18A 1123 33.0 19P Propolis −24.9

[0046] In certain embodiments, the As26, J229, J91, LL27, LL23, HM7, As25, MT26, and J205 analogues decrease the levels of several key proteins in cereblon pathway including the protein, IRF4. In certain embodiments, the analogues of Table 1 decrease the levels of several key genes in cereblon pathway including the gene, IRF4. In certain embodiments, the analogues of Table 1 decrease the levels of several key proteins in cereblon pathway including the protein, Ikaros. In certain embodiments, the analogues of Table 1 decrease the levels of several key genes in cereblon pathway including the gene, Ikaros. In certain embodiments, the analogues of Table 1 exhibit remarkable cell growth inhibitory activity on myeloma and lymphoma cell lines that are non-responsive to lenalidomide. In other embodiments of the present invention, analogues, other than the 18 analogues of Table 1, derived using Scheme 1 may also be used in the present invention.

[0047] Referring to FIG. 5A to FIG. 5F, As26 exhibited superior myeloma cell growth inhibitory effect in comparison to IMiDs, CAPE, and analogs GL8 and J229. Myeloma cell lines were treated for 3 or 5 days with increasing concentration of lenalidomide (FIG. 5A) and pomalidomide (FIG. 5B). KMM1 cells (FIG. 5D), MM1R cells (FIG. 5E), and JJN3 cells (FIG. 5F) were treated for 48 hours with varying concentration of CAPE, GL8, As26 and J229. The cell growth inhibition was determined by PrestoBlue cell viability assay. Data from three independent experiments is presented as mean±SD. IC50 values (FIG. 5C) representing half-maximal inhibitory concentration of compounds were determined using GraphPad prism analyses software.

[0048] Induction of apoptosis in myeloma cells by various inhibitors was determined by staining exposed phosphatidylserine with Annexin V-FITC and DNA with Propidium iodide using Alexa Fluor® 488 annexin V/Dead Cell Apoptosis Kit (Invitrogen, ThermoFisher Scientific, CA) according to the manufacturer's instructions. Single-cell suspensions were analyzed on a Beckmann Coulter Gallios Flow Cytometer with Kaluza analyses software. Twenty-five thousand events were acquired for every condition. Apoptotic cells were scored as Annexin V+, PI− and Annexin V+, PI+.

[0049] Referring to FIG. 6, Apoptotic effect of veh/vehicle (DMSO), lenalidomide (len), pomalidomide (pom), CAPE, GL8, As26 and J229 (all compounds at 10 uM concentration) on KMM1 cells upon 72-hour treatment followed by Annexin V-PI flow cytometry analyses is shown. Percentage of early and late apoptotic cells are presented as mean±SD (*P≤0.05; **P≤0.01). Remarkable apoptotic effect by As26 can be observed.

[0050] Referring to FIGS. 7A to FIG. 7C, lymphoma cell growth inhibitory effect in comparison to 3-day treatment of IMiDs (FIG. 7A), 5-day treatment of IMiDs (FIG. 7B) and 2-day or 48 hr treatment of GL8, J229, LL23, As25 and HM7 on U2932 Lymphoma cell line determined by PrestoBlue cell viability assays (FIG. 7C).

[0051] Referring to FIG. 8, an immunoblot showing the protein expression of IRF4 in human cell lines and myeloma patient samples is provided. Specific expression of IRF4 in CD138 positive cells isolated from the myeloma patient can be observed. The mononuclear cells from early stage of myeloma, namely monoclonal gammopathy of undetermined significance (MGUS), shows no expression of IRF4.

[0052] Referring to FIG. 9, an immunoblot showing the effect of lenalidomide (IMiD), CAPE, GL8, As26 and J229 on human myeloma cell line MM1R is provided. Lenalidomide, CAPE and other analogs at indicated concentrations were added to MMIR cells for 48 hours. Proteins extracts from control and treated conditions were subjected to electrophoresis followed by immunoblotting, and membrane probed sequentially using IRF4, IKZF1, IKZF3 and beta-actin antibodies, while beta-actin was used as the protein loading control.

[0053] For use in therapy a therapeutically effective amount of As26, J229, J91, LL27, LL23, HM7, As25, MT26, or J205 or pharmaceutically acceptable salts or solvates thereof, may be presented as a pharmaceutical composition. Thus, in a further embodiment the invention provides a pharmaceutical composition of As26, J229, J91, LL27, LL23, HM7, As25, MT26, or J205 or pharmaceutically acceptable salts or solvates thereof in admixture with one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0054] When applicable, the compositions of the present invention, including As26, J229, J91, LL27, LL23, HM7, As25, MT26, or J205 may be in the form of and/or may be administered as a pharmaceutically acceptable salt.

[0055] Typically, a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

[0056] Suitable addition salts are formed from acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate acetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharinate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and isethionate.

[0057] Suitable salts may also be formed from bases, forming salts including ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium. Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, using conventional methods.

[0058] Pharmaceutical compositions of the invention may be formulated for administration by any appropriate route. Therefore, the pharmaceutical compositions of the invention may be formulated, for example, as tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral solutions or suspensions. Such pharmaceutical formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

[0059] Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan, monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

[0060] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question.

[0061] The compositions of the present invention may be suitable for the treatment of diseases in a human or animal patient. In one embodiment, the patient is a mammal including a human, horse, dog, cat, sheep, cow, or primate. In one embodiment the patient is a human. In a further embodiment, the patient is not a human.

[0062] As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0063] As used herein the term “treatment” refers to defending against or inhibiting a symptom, treating a symptom, delaying the appearance of a symptom, reducing the severity of the development of a symptom, and/or reducing the number or type of symptoms suffered by an individual, as compared to not administering a pharmaceutical composition of the invention. The term treatment encompasses the use in a palliative setting

[0064] The present invention, in another embodiment, relates to a use of a pharmaceutical composition including As26, J229, J91, LL27, LL23, HM7, As25, MT26, or J205 or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents and excipients for the treatment of blood cancers.

REFERENCES

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