Inhibitors of phospholipid synthesis and methods of use
Inhibitors of Glycerol 3-Phosphate Acyltransferase (GPAT) are provided; and methods of use in the treatment of cancer; and treatment of conditions relating to metabolic syndrome and hyperlipidemia.
1. A GPAT inhibitor of one of formulae (IA), (IB), (IC):
wherein:
R 1 is selected from deuterated alkyl and substituted deuterated alkyl;
R 2 , and R 3 are each independently selected from alkyl, substituted alkyl, deuterated alkyl and substituted deuterated alkyl;
or a pharmaceutically acceptable salt or solvate thereof.
2. The GPAT inhibitor of claim 1 , selected from the compounds:
3. A pharmaceutical composition, comprising:
a GPAT inhibitor of claim 1 ; and
a pharmaceutically acceptable excipient.
4. A method of treating a subject for cancer, the method comprising:
administering an effective dose of a GPAT inhibitor according to claim 1 for a period of time sufficient to inhibit growth of the cancer.
5. The method of claim 4 , wherein the cancer is a MYC-dependent cancer.
6. The method of claim 4 , wherein the cancer is selected from renal cell carcinoma, hepatocellular carcinoma, and lymphoma.
7. The method of claim 4 , wherein the cancer is a hepatic cancer.
8. The method of claim 4 , wherein the cancer is a lipogenesis-dependent neoplasm.
9. The method of claim 4 , comprising:
comparing a lipogenesis profile obtained from a subject having a neoplasm with a reference lipogenesis profile to classify whether the neoplasm is lipogenesis-dependent; and administering to the subject an effective amount of a GPAT inhibitor of claim 1 , when the neoplasm is classified as lipogenesis-dependent, to treat the subject for the lipogenesis-dependent neoplasm.
10. The method of claim 4 , wherein the subject is a mammal.
11. The method of claim 10 , wherein the mammal is a human.
12. A method of treating a metabolic syndrome related disease, the method comprising:
administering to a subject an effective dose of a GPAT inhibitor according to claim 1 for a period of time sufficient to reduce symptoms of the disease in the subject.
13. The method of claim 12 , wherein the disease is selected from hyperlipidemia, metabolic syndrome, type 2 diabetes, fatty liver disease and obesity.
14. The method of claim 13 , wherein the disease is obesity.
15. The method of claim 12 , wherein the subject is a mammal.
16. The method of claim 15 , wherein the mammal is a human.