Inhibition of glutaminase C

1. A method of treating a subject with a condition mediated by production of glutamate from glutamine by glutaminase C, said method comprising:

selecting a subject with a condition mediated by production of glutamate from glutamine by glutaminase C, wherein the condition is breast cancer; and

administering to said selected subject an inhibitor of glutaminase C activity under conditions effective to treat said breast cancer, wherein the inhibitor is a compound of Formula I:

wherein:

the dotted circle identifies an active moiety;

X is independently —CR 14a — or N;

R 1a is independently 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 2a , 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 substituents 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, mono or polycyclic aryl, each one of R 11a -R 17a optionally substituted with NH 2 , OH, halogen, COOH, NO 2 and CN.

2. The method of claim 1 , wherein the inhibitor inhibits phosphorylation of glutaminase C.

3. The method of claim 1 , wherein the inhibitor inhibits expression-independent glutaminase C activity and/or glutaminase C activity independent of exogenous phosphate addition.

4. The method of claim 1 , wherein the compound comprises an active moiety of formula:

5. The method of claim 1 , wherein said administering is performed parenterally, orally, subcutaneously, intravenously, intramuscularly, extraperitoneally, by intranasal instillation, or by application to mucous membranes.