INHIBITION AND TREATMENT OF PROSTATE CANCER METASTASIS

• US 20090124569A1
• Filed: 10/13/2008
• Published: 05/14/2009
• Est. Priority Date: 10/12/2007
• Status: Abandoned Application

• Current Assignee: Northwestern University
• Original Assignee: Northwestern University
• Inventors: Scheidt, Karl A., Bergan, Raymond C.
• Application Number:
  US12/250,351
• Publication Number:
  US 20090124569A1
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/51 Thiamines, e.g. vitamin B1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07D 311/36 not hydrogenated in the hetero ring, e.g. isoflavones

Abstract

The present invention provides compounds and methods of inhibiting and treating metastatic prostate cancer. The compounds include MEK4 inhibitors. In another aspect the invention provides methods of identifying inhibitors of metastatic prostate cancer by screening for inhibitors of MEK4.

Claims

1. A method for inhibiting prostate cancer metastasis, comprising:

administering a compound having formula;

2. The method of claim 1, wherein, if Z is H, one of R₇ or R₈ is OH or OCH₃.

3. The method of claim 1, wherein R₃, R₄, R₅, and R₆ are each H.

4. The method of claim 1, wherein Z is OCH₃, halogen, or H.

5. The method of claim 1, wherein said subject is a human.

6. The method of claim 1, wherein the compound is administered prior to surgical removal of a tumor.

7. The method of claim 1, wherein the compound is administered after surgical removal of a tumor.

8. The method of claim 1, wherein the compound is co-administered with a different prostate cancer therapeutic agent.

9. A method for inhibiting prostate cancer metastasis, comprising:

administering a MEK4 pathway inhibitor to a subject having prostate cancer, wherein the MEK4 pathway inhibitor is not genistein.

10. The method of claim 9, wherein said inhibitor is a MEK4 inhibitor.

11. The method of claim 9, wherein said MEK4 pathway inhibitor is an RNAi molecule that inhibits the expression of MEK4.

12. The method of claim 9, wherein said MEK4 pathway inhibitor is an antisense oligonucleotide that inhibits the expression of MEK4.

13. The method of claim 9, wherein said MEK4 pathway inhibitor is a small molecule drug.

14. The method of claim 9, further comprising administering an endoglin pathway activator to the said subject.

15. A method for inhibiting prostate cancer cell invasion or migration, comprising:

exposing a prostate cancer cell to a MEK4 pathway inhibitor, wherein said compound is not genistein.

16. The method of claim 15, wherein said inhibitor is a MEK4 inhibitor.

17. The method of claim 15, wherein said prostate cancer cell is a cultured cell.

18. The method of claim 15, wherein said prostate cancer cell is a xenograft transplant.

19. The method of claim 15, wherein said prostate cancer cell is obtained from a tissue biopsy from a subject having prostate cancer.

20. A method of inhibiting MEK4 in vitro, comprising:

administering a compound having formula;

21. The method of claim 20, further comprising the step of detecting MEK4 enzyme activity.

22. The method of claim 21, wherein said MEK4 enzyme activity comprises detecting activity of a MEK4 enzyme pathway member.

23. The method of claim 22, wherein said MEK4 enzyme pathway member is selected from the group consisting of:

p38 MAPK, MAPK APK2, HSP 27, or MMP-2.

24. A method for identifying compounds that inhibit prostate cancer metastasis, comprising:

exposing a sample comprising MEK4 to a candidate compound and determining MEK4 enzyme activity.

25. The method of claim 24, wherein said sample comprises a cell.

26. The method of claim 25, wherein said cell resided in a subject.

27. The method of claim 24, wherein said determining MEK4 enzyme activity comprises identifying metastasis.

28. The method of claim 24, wherein said determining MEK4 enzyme activity comprises measuring modification of a MEK4 substrate.

29. A pharmaceutical preparation comprising a compound having formula:

30. The composition of claim 29 wherein, if Z is H, one of R₇ or R₈ is OH or OCH₃.

31. The composition of claim 29, wherein R₃, R₄, R₅, and R₆ are each H.

32. The composition of claim 29, wherein Z is OCH₃, halogen, or H.