Inhibition of glutaminase C

1. A method of reducing the production of glutamate from glutamine by glutaminase C in a cancerous cell or a cancerous tissue, said method comprising:

inhibiting glutaminase C activity in the cancerous cell or cancerous tissue under conditions effective to reduce production of glutamate from glutamine, wherein said inhibiting comprises:

selecting a cancerous cell or a cancerous tissue, wherein the cancer is characterized by glutaminase C hyperactivity and/or glutaminase C overexpression;

providing a compound of formula (I):

wherein:

the dotted circle identifies an active moiety;

X is independently —CR 14a — or N;

R 1a is H, OH, OR 14a , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 14a C(O)—, R 14a OC(O)—, R 14a S(O)—, or R 14a S(O) 2 —;

R 2 , R 3a , R 4a , R 5a , and R 6a are each independently H, halogen, NO 2 , OH, OR 14a , —SR 14a , NH 2 , NHR 14a , NR 14a R 15a , R 14a C(O)—, R 14a OC(O)—, R 14a C(O)O—, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl with each cyclic unit containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; or

R 2a and R 3a , R 3a and R 4a , R 4a and R 5a , or R 5a and R 6a can combine to form a heterocyclic ring;

R 7a , R 8a , R 9a , and R 10a are each independently H, OH, NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl with each cyclic unit containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the aryl, heteroaryl, and aryl C 1 -C 6 alkyl are optionally substituted from 1 to 3 times with substitutents selected from the group consisting of halogen, OH, NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, SH, and C 1 -C 6 thioalkyl; and

R 11a , R 12a , R 13a , R 14a , R 15a , R 16a , and R 17a are each independently H, halogen, OH, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl C 1 -C 6 alkyl, or mono or polycyclic aryl, wherein each one of R 11a -R 17a is optionally substituted with NH 2 , OH, halogen, COOH, NO 2 , or CN; and

contacting glutaminase C in the cancerous cell or cancerous tissue with said compound, wherein the production of glutamate from glutamine in the cancerous cell or cancerous tissue is reduced; and

wherein said inhibiting is carried out under conditions effective to inhibit growth of the cancerous cell or cancerous tissue.

2. The method of claim 1 , wherein the active moiety is:

3. The method of claim 1 , wherein said inhibiting is carried out by inhibiting an activating phosphorylation event on glutaminase C.

4. The method of claim 1 , wherein said inhibiting is carried out by inhibiting overexpression-independent glutaminase C activity and/or inhibiting glutaminase C activity independent of exogenous phosphate addition.

5. The method of claim 1 , wherein said inhibiting is carried out by inhibiting glutaminase C hyperactivity.

6. The method of claim 1 , wherein the compound is compound 968:

7. The method of claim 6 , wherein the cancer is characterized by glutaminase C hyperactivity and glutaminase C overexpression.

8. The method of claim 6 , wherein the cancer is characterized by glutaminase C hyperactivity without glutaminase C overexpression.

9. The method of claim 6 , wherein the cancer is breast cancer, lung cancer, brain cancer, or colon cancer.

10. The method of claim 9 , wherein the cancer is a triple negative breast cancer.

11. The method of claim 1 , wherein the cancer is characterized by glutaminase C hyperactivity and glutaminase C overexpression.

12. The method of claim 1 , wherein the cancer is characterized by glutaminase C hyperactivity without glutaminase C overexpression.

13. The method of claim 1 , wherein the cancer is breast cancer, lung cancer, brain cancer, or colon cancer.

14. The method of claim 13 , wherein the cancer is a triple negative breast cancer.