Method for treating cell proliferation related disorders

1. A method of treating a subject having a cell proliferation-related disorder characterized by the presence of a mutant isocitrate dehydrogenase 2 enzyme having a mutation at residue 140 (IDH2R140X), the method comprising administering to the subject a therapeutically effective amount of an inhibitor of said mutant isocitrate dehydrogenase 2 enzyme or a pharmaceutically acceptable salt thereof having the formula (XI) wherein:

W, X, Y and Z are each independently selected from CH or N;

B and B 1 are independently selected from hydrogen, alkyl or when taken together with the carbon to which they are attached form a carbonyl group;

Q is C═O or SO 2 ;

D and D 1 are independently selected from a bond, oxygen or NR c ;

A is optionally substituted aryl or optionally substituted heteroaryl;

R 1 is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, aralkyl, and heteroaralkyl; each of which may be optionally substituted with 0-3 occurrences of R d ;

each R 3 is independently selected from halo, haloalkyl, alkyl and —OR a ;

each R a is independently selected from alkyl, and haloalkyl;

each R b is independently alkyl;

each R c is independently selected from hydrogen and alkyl;

each R d is independently selected from halo, haloalkyl, alkyl, nitro, cyano, and OR a , or two R d taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;

n is 0, 1, or 2;

h is 0, 1, 2; and

g is 0, 1 or 2.

2. The method of claim 1 , wherein the inhibitor binds to IDH2R140X and inhibits neoactivity, wherein the neoactivity is the ability to convert alpha-ketoglutarate to 2-hydroxyglutarate (2HG).

3. The method of claim 1 , wherein IDH2R140X is detected in a sample obtained from the subject.

4. The method of claim 3 , wherein the sample comprises tissue, product or bodily fluid.

5. The method of claim 1 , wherein IDH2R140X is detected by sequencing a nucleic acid from an affected cell that encodes the relevant amino acid(s) from IDH2R140X.

6. The method of claim 5 , wherein the sequencing is performed by polymerase chain reaction (PCR).

7. The method of claim 1 , wherein IDH2R140X is selected from IDH2R140Q, IDH2R140W, and IDH2R140L.

8. The method of claim 1 , wherein IDH2R140X is IDH2R140Q.

9. The method of claim 1 , wherein the cell proliferation-related disorder is selected from the group consisting of a tumor of the CNS, a leukemia, prostate cancer, fibrosarcoma, paraganglioma, follicular thyroid cancer, myeloma, thyroid cancer, sarcoma, osteosarcoma, myeloproliferative neoplasms, and myelodysplastic syndrome (myelodysplasia).

10. The method of claim 9 , wherein the cell proliferation-related disorder is myelodysplastic syndrome.

11. The method of claim 9 , wherein the leukemia is acute myelogenous lymphoplastic leukemia (AML) or acute lymphoblastic leukemia (ALL).

12. The method of claim 9 , wherein the cell proliferation-related disorder is acute myelogenous leukemia (AML).

13. The method of claim 11 , wherein the ALL is B-cell ALL or T-cell ALL.

14. The method of claim 9 , wherein the myeloproliferative neoplasm is chronic myelogenous leukemia (CML).