Methods for cancer therapy and stem cell modulation

• US 8,058,258 B2
• Filed: 11/15/2006
• Issued: 11/15/2011
• Est. Priority Date: 03/02/2006
• Status: Expired due to Fees

• Current Assignee: Agency For Science Technology and Research
• Original Assignee: Agency For Science Technology and Research
• Inventors: Tan, Jing, Yang, Xiao Jing, Yu, Qiang
• Primary Examiner(s): Lewis; Patrick
• Application Number:
  US12/281,470
• Publication Number:
  US 20100075915A1
• Time in Patent Office: 1,826 Days
• Field of Search: None
• US Class Current: 514/45
• 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. An epigenetic method of inducing apoptosis in a tumour cell by inhibition of histone methylation, said method comprising administering to said tumour cell a compound of the general formula (I)

2. The method of claim 1, wherein said tumour cell is cultured.

3. The method of claim 1, wherein said tumour cell is a breast cancer cell.

4. The method of claim 3, wherein said cell is a cell selected from the group of cell lines consisting of MCF-7, MB-468, SK-BR-3, and T47D.

5. The method of claim 1, further comprising determining apoptosis in said tumour cell.

6. The method of claim 1, wherein said tumour cell is obtained from a mammal.

7. The method of claim 1, wherein said tumour cell is comprised in a mammal.

8. The method of claim 6, wherein the mammal is selected from the group consisting of a rat, a mouse, a cow, a pig and a human.

9. The method of claim 1, comprising contacting said tumour cell with a predetermined quantity of a compound of the general formula (I).

10. The method of claim 1, 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.

11. The method of claim 10, wherein the first tumour cell and the second tumour cell are obtained from the same patient.

12. The method of claim 11, wherein said method is a method for predicting a patient'"'"'s individual response to a compound of the general formula (I).

13. The method of claim 1, wherein said inhibition of histone methylation comprises an inhibition of methylation of lysine 27 on histone 3.

14. The method of claim 1, wherein said inhibition of histone methylation comprises depleting in the respective cell a polycomb repressive complex.

15. The method of claim 14, further comprising measuring the levels of at least one component of at least one polycomb repressive complex.

16. The method of claim 15, 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.

17. The method of claim 14, wherein depleting said polycomb repressive complex releases a complex between said polycomb repressive complex and a tumour suppressor gene.

18. The method of claim 17, wherein apoptosis is achieved by means of reactivating a tumour suppressor gene.

19. The method of claim 18, wherein said tumour suppressor gene is FBX032.

20. The method of claim 19, further comprising measuring the expression of FBX032 in the respective cell.

21. The method of claim 20, further comprising comparing the result of the measurement of FBX032 expression with that of a control measurement.

22. The method of claim 1, wherein said inhibition of histone methylation comprises modulating gene expression in a cell that expresses the components of a polycomb repressive complex.

23. The method of claim 22, wherein said polycomb repressive complex is at least one of polycomb repressive complex 2, polycomb repressive complex 3, and polycomb repressive complex 4.

24. The method of claim 22, wherein the cell is a recombinant cell comprising a target gene under the control of the promoter of the FBX032 gene.

25. The method of claim 22, 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.

26. The method of claim 1 wherein the step of administering comprises administering the compound of general formula (I) to a patient comprising said tumour cell.