METABOLIC INHIBITOR AGAINST TUMORS HAVING AN IDH MUTATION

• US 20130109643A1
• Filed: 05/10/2011
• Published: 05/02/2013
• Est. Priority Date: 05/10/2010
• Status: Abandoned Application

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Tsukamoto, Takashi, Emadi, Ashkan, Riggins, Gregory Joseph, Dang, Chi Van, Seltzer, Meghan Joyce
• Application Number:
  US13/697,097
• Publication Number:
  US 20130109643A1
• Time in Patent Office: Days
• US Class Current: 514/34
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Methods for treating a cancer having a mutant isocitrate dehydrogenase (IDH), including, but not limited to, a malignant low-grade glioma, a secondary glioblastoma, a transforming myeloproliferative disorder (tMPD), and an acute myelogenous leukemia (AML), with a glutaminase inhibitor, including, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), are disclosed.

Claims

1. A method for treating a cancer having a mutant isocitrate dehydrogenase (IDH) in a subject in need of treatment thereof, the method comprising administering to the subject a therapeutically effective amount of a glutaminase inhibitor.

2. The method of claim 1, wherein the glutaminase inhibitor is selected from the group consisting of:

(a) a compound of Formula (I);

3. The method of claim 2, wherein the glutaminase inhibitor is a compound of Formula (I) and X is sulfur.

4. The method of claim 3, wherein each of R₁ and R₂ is —

(CH₂)_n-aryl.

5. The method of claim 3, wherein each of R₁ and R₂ is 2-thiophenyl.

6. The method of claim 3, wherein each of R₁ and R₂ is 2-furanyl.

7. The method of claim 3, wherein each of R₁ and R₂ is phenyl or benzyl, unsubstituted or substituted with lower alkyl or lower alkoxyl.

8. The method of claim 7, wherein each of R₁ and R₂ is benzyl.

9. The method of claim 7, wherein each of R₁ and R₂ is p-methoxy phenyl.

10. The method of claim 7, wherein each of R₁ and R₂ is m-tolyl.

11. The method of claim 2, wherein the glutaminase inhibitor is a compound of Formula (I) and each of R₁ and R₂ is lower alkoxyl.

12. The method of claim 11, wherein each of R₁ and R₂ is ethoxy.

13. The method of claim 2, wherein the glutaminase inhibitor is a compound of Formula (I) and each of R₁ and R₂ is lower alkyl.

14. The method of claim 13, wherein each of R₁ and R₂ is t-butyl.

15. The method of claim 2, wherein the compound of Formula (I) is bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES):

16. The method of claim 1, wherein the mutant IDH is selected from the group consisting of mutant IDH1 and mutant IDH2.

17. The method of claim 1, wherein the cancer is selected from the group consisting of a malignant low-grade glioma, a secondary glioblastoma, a transforming myeloproliferative disorder (tMPD), and an acute myelogenous leukemia (AML).

18. The method of claim 1, further comprising administering the glutaminase inhibitor in combination with one or more of an antimetabolite, an anthracycline, and combinations thereof.

19. A method for selectively inhibiting growth of a cell expressing mutant isocitrate dehydrogenase (IDH), the method comprising administering to the cell an effective amount of a glutaminase inhibitor.

20. The method of claim 19, wherein the glutaminase inhibitor is selected from the group consisting of:

(a) a compound of Formula (I);

21. The method of claim 20, wherein the mutant IDH is selected from the group consisting of mutant IDH1 and mutant IDH2.

22. The method of claim 20, wherein the cell comprises a cancer cell.

23. The method of claim 22, wherein the cancer cell is selected from the group consisting of a malignant low-grade glioma, a secondary glioblastoma, and an acute myelogenous leukemia (AML).

24. A method for selecting a subject for treatment with a glutaminase inhibitor, the method comprising measuring a 2-hydroxyglutarate (2-HG) level in a biological sample from the subject and selecting the subject for treatment if the 2-HG level exceeds a predetermined threshold value.

25. The method of claim 24, wherein the biological sample comprises serum.

26. The method of claim 24, wherein the subject is afflicted with or is suspected of being afflicted with a cancer.

27. The method of claim 26, wherein the cancer is selected from the group consisting of a malignant low-grade glioma, a secondary glioblastoma, a transforming myeloproliferative disorder, and an acute myelogenous leukemia (AML).

28. The method of claim 24, further comprising stratifying the subject based on the 2-HG level in the biological sample.

29. A method for selecting a subject for treatment with a glutaminase inhibitor, the method comprising identifying the presence of a IDH1 or IDH2 mutation in a cell or tissue from the subject and selecting the subject for treatment with a glutaminase inhibitor.

30. The method of claim 29, wherein the method further comprises identifying the presence of an FLT3 mutation in the subject.

31. A method for monitoring a treatment of a subject with a glutaminase inhibitor, the method comprising measuring a 2-HG level in a biological sample from the subject and comparing the 2-HG level in the subject with a 2-HG level selected from the group consisting of a 2-HG level in a previous biological sample from the subject, a predetermined threshold value of 2-HG, a 2-HG level in one or more biological samples from a control group, and combinations thereof.

32. A method for detecting transformation in a subject afflicted with a myeloproliferative disorder (MPD), the method comprising measuring a 2-HG level in a biological sample from the subject and comparing the 2-HG level with a predetermined threshold value to detect transformation.

33. The method of claim 32 further comprising prophylactic treatment of the subject with a glutaminase inhibitor.

34. The method of claim 33, wherein the glutaminase inhibitor is selected from the group consisting of:

(a) compound of Formula (I);