METHODS OF IDENTIFYING A CANDIDATE COMPOUND

• US 20130197106A1
• Filed: 03/31/2011
• Published: 08/01/2013
• Est. Priority Date: 04/01/2010
• Status: Abandoned Application

• Current Assignee: Servier Pharmaceuticals LLC (Servier Sas)
• Original Assignee: Agios Pharmaceuticals Inc.
• Inventors: Fantin, Valeria, Su, Shin-San Michael
• Application Number:
  US13/638,881
• Publication Number:
  US 20130197106A1
• Time in Patent Office: Days
• US Class Current: 514/789
• CPC Class Codes: C12Q 1/32 involving dehydrogenase
• CPC Class Codes: G01N 2333/904 acting on CHOH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity

Abstract

The invention relates to methods identifying compounds for the treatment of cell proliferation-related disorders, e.g., proliferative disorders such as cancer.

Claims

1. A method of identifying a candidate compound that selectively interferes with proliferation or viability of a first IDH (isocitrate dehydrogenase)-mutant cell that has elevated levels of 2HG (2-hydroxyglutarate) comprising contacting a candidate compound with a first IDH-mutant cell that has elevated levels of 2HG, and if proliferation or viability of the first IDH-mutant cell that has elevated levels 2HG is decreased as compared to a control cell that does not have elevated levels of 2HG, then identifying the candidate compound as a compound that interferes with proliferation or viability of the first IDH-mutant cell.

2. The method of claim 1, wherein the first IDH-mutant cell carries a mutation in the IDH1 gene.

3. The method of claim 1, wherein the first IDH-mutant cell carries a mutation in the IDH2 gene.

4. The method of claim 1, wherein the first IDH-mutant cell carries an IDH1^R132X mutation.

5. The method of claim 1, wherein the first IDH-mutant cell carries an IDH2^R172X mutation.

6. The method of claim 1, wherein the first IDH-mutant cell carries an IDH1^R132H mutation.

7. The method of claim 1, wherein the first IDH-mutant cell carries an IDH2^R172K mutation.

8. The method of claim 1, wherein the first IDH-mutant cell carries an IDH1^R132C mutation.

9. The method of claim 1, wherein the first IDH-mutant cell carries an IDH2 ^R140Q mutation.

10. The method of claim 1, wherein the first IDH-mutant cell carries any one of the mutations listed in Table 1.

11. The method of claim 1, wherein the first IDH-mutant cell is from a cancer cell line.

12. The method of claim 1, wherein the first IDH-mutant cell is from a glioma cell line or a fibrosarcoma cell line.

13. The method of claim 1, wherein the first IDH-mutant cell is from a U87 glioma cell line.

14. The method of claim 1, wherein the first IDH-mutant cell is from a U87 glioma cell line engineered to express IDH1^R132H.

15. The method of claim 1, wherein the first IDH-mutant cell is from a fibrosarcoma /HT1080 cell line that carries an IDH1^R132C mutant gene.

16. The method of claim 14, wherein the control cell is a parental U87 cell.

17. The method of claim 15, wherein the control cell is a fibrosarcoma HT1080 cell engineered to expressed a microRNA, siRNA, or antisense RNA that inhibits expression of the IDH1^R132C mutant gene.

18. The method of claim 1, further comprising testing the candidate compound for tumor suppressor activity in an animal model.

19. The method of claim 1, further comprising administering the compound to a human who has a cancer, in an amount sufficient to treat the cancer.

20. The method of claim 1, wherein the cell proliferation is assayed by luminescence.

21. The method of claim 1, wherein the candidate compound is obtained from a library.

22. The method of claim 1, further comprising testing the selected candidate compound for an ability to selectively interfere with proliferation or viability of a second IDH-mutant cell comprising contacting the selected candidate compound with a second IDH-mutant cell that has elevated levels of 2HG, and if proliferation or viability of the second IDH-mutant cell is decreased as compared to a second control cell that does not have elevated levels of 2HG, then identifying the candidate compound again as a compound that selectively interferes with proliferation or viability of the first IDH-mutant cell.

23. The method of claim 22, wherein the first IDH-mutant cell is from a U87 cell line that carries an IDH1^R132H mutation, and the second IDH-mutant cell line is an HT1080 cell line.

24. A method of identifying a compound that specifically interferes with an IDH (isocitrate dehydrogenase)-mutant enzyme that causes elevated levels of 2HG (2-hydroxyglutarate) comprising contacting a candidate compound with an IDH-mutant cell that has elevated levels of 2HG, and if 2HG levels are decreased as compared to a control cell that does not have elevated levels of 2HG, then identifying the candidate compound as a compound that specifically interferes with the IDH-mutant enzyme.

25. The method of claim 24, wherein 2-HG production is assayed by an enzymatic fluorescence assay.

26. The method of claim 24, further comprising testing the selected candidate compound for an ability to selectively interfere with proliferation or viability of the IDH-mutant cell, comprising contacting the selected candidate compound with the IDH-mutant cell, and if proliferation or viability of the IDH-mutant cell is decreased as compared to the control cell, then identifying the candidate compound as a compound that selectively interferes with proliferation of the IDH-mutant cell.