METHODS FOR CANCER THERAPY AND STEM CELL MODULATION

• US 20100075915A1
• Filed: 11/15/2006
• Published: 03/25/2010
• Est. Priority Date: 03/02/2006
• Status: Active Grant

• Current Assignee: Agency For Science Technology and Research
• Original Assignee: Agency For Science Technology and Research
• Inventors: Yu, Qiang, Tan, Jing, Yang, Xiao Jing
• Granted Patent: US 8,058,258 B2
• Time in Patent Office: Days
• US Class Current: 514/49
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to a method of inducing apoptosis in a tumour cell as well as modulating pluripotency and/or self-renewing characteristics of a stem/progenitor cell. The method comprises administering to the respective cell a compound of general formula (I). In general formula A is C or N. R¹, R⁴ and R⁵ are, independently selected, H or aliphatic, cycloaliphatic aromatic, arylaliphatic, or arylcycloaliphatic hydrocarbyl groups, that comprise 0-3 heteroatoms being N, O, S, or Si. R⁴ and R⁵ may optionally be linked so as to define an aliphatic hydrocarbyl bridge. R² is H or a halogen, such as F or Cl. R³ is H, or an aliphatic or arylaliphatic hydrocarbyl group comprising 1-8 main chain carbon atoms and 0-3 heteroatoms being N, O, S, Si, or a halogen such as Cl or F. Also provided is a pharmaceutical composition for inducing apoptosis in a tumour cell and/or modulating pluripotency and/or self-renewing characteristics of a stem/progenitor cell. The pharmaceutical composition comprises a compound as defined above or a pharmaceutically acceptable salt thereof and a carrier or diluent.

Claims

1-23. -23. (canceled)

24. A pharmaceutical composition, comprising

(a) a compound of formula (I) or a pharmaceutically acceptable salt thereof,

25. The pharmaceutical composition of claim 24, further comprising a DNA methyltransferase inhibitor, a DNA demethylating agent, and/or a histone-deacetylase inhibitor.

26. The pharmaceutical composition of claim 25, wherein said DNA methyltransferase inhibitor is selected from the group consisting of 5-azacytidine, decitabine (5-aza-2′

-deoxycytidine), 5-fluoro-2′

-deoxycytidine, 5,6-dihydro-5-azacytidine, and zebularine.

27. The pharmaceutical composition of claim 25, wherein said DNA demethylating agent is selected from the group consisting of hydralazine, procainamide, procaine, (−

)-epigallocatechin-3-gallate (EGCG), psammaplin A, the oligodeoxynucleotide MB98, and 2-(1,3-Dioxo-1,3-dihydro-2H-isoindo1-2-yl)-3-(1H-indo1-3-yl (MG98).

28. The pharmaceutical composition of claim 25, wherein said histone-deacetylase inhibitor is selected from the group consisting of butyrate, phenylbutyrate, valproic acid, m-carboxycinnamic acid bishydroxamic acid (CBHA), oxamflatin, PDX-101, MS-275, depsipeptide, pyroxamide, scriptaid, suberoylanilide hydroxyamic acid (SAHA), trichostatin (TSA), NVP-LAQ824, LBH589, apicidin, CHAP, trapoxin, N-acetyldinaline, and MS-275.

29. A method of inducing apoptosis in a tumour cell, said method comprising administering to said tumour cell a compound of the general formula (I)

30. The method of claim 29, wherein said tumour cell is cultured.

31. The method of claim 29, wherein said tumour cell is a breast cancer cell.

33. The method of claim 29, further comprising determining apoptosis in said tumour cell.

34. The method of claim 29, wherein said tumour cell is obtained from a mammal.

35. The method of claim 29, wherein said tumour cell is comprised in a mammal.

36. The method of claim 34, wherein the mammal is selected from the group consisting of a rat, a mouse, a cow, a pig and a human.

37. The method of claim 29, comprising contacting said tumour cell with a predetermined quantity of a compound of the general formula (I).

38. The method of claim 29, comprising the use of at least two different predetermined quantities of a compound of the general formula (I) and at least a first and a second tumour cell, wherein the first tumour cell is contacted with the lower of the two predetermined quantities and the second tumour cell is contacted with the higher of the two predetermined quantities.

39. The method of claim 38, wherein the first tumour cell and the second tumour cell are obtained from the same patient.

40. The method of claim 39, wherein said method is a method for predicting a patient'"'"'s individual response to a compound of the general formula (I).

41. The method of claim 29, wherein said method is an in epigenetic method.

42. The method of claim 41, wherein inducing apoptosis in a tumour cell comprises an inhibition of histone methylation.

43. The method of claim 42, wherein said inhibition of histone methylation comprises an inhibition of methylation of lysine 27 on histone 3.

44. The method of claim 42, wherein said inhibition of histone methylation comprises depleting in the respective cell a polycomb repressive complex.

45. The method of claim 44, further comprising measuring the levels of at least one component of at least one polycomb repressive complex.

46. The method of claim 45, further comprising comparing the result of the measurement of levels of said at least one component of at least one polycomb repressive complex with that of a control measurement.

47. The method of claim 44, wherein depleting said polycomb repressive complex releases a complex between said polycomb repressive complex and a tumour suppressor gene.

48. The method of claim 47, wherein apoptosis is achieved by means of reactivating a tumour suppressor gene.

49. The method of claim 48, wherein said tumour suppressor gene is FBX032.

50. The method of claim 49, further comprising measuring the expression of FBX032 in the respective cell.

51. The method of claim 50, further comprising comparing the result of the measurement of FBX032 expression with that of a control measurement.

72. The method of claim 29 wherein the step of administering comprises administering the compound of general formula (I) to a patient comprising said tumour cell.

52-65. -65. (canceled)

66. A method for modulating gene expression in a cell that expresses the components of a polycomb repressive complex, said method comprising administering to said cell a compound of the general formula (I)

67. The method of claim 66, wherein said polycomb repressive complex is at least one of polycomb repressive complex 2, polycomb repressive complex 3, and polycomb repressive complex 4.

68. The method of claim 66, wherein the cell is a stem/progenitor cell or a primordial germ cell.

69. The method of claim 68, wherein the stem cell is an embryonic stem cell.

70. The method of claim 66, wherein the cell is a recombinant cell comprising a target gene under the control of the promoter of the FBX032 gene.

71. The method of claim 66, wherein the target gene, the expression of which is modulated, is any one of a reporter gene, a drug resistance gene, an apoptosis gene (so-called ‘

death’

gene), or any other gene with desirable expression in a respective cell.