Fatty acid synthase inhibitors
The present disclosure relates to a method for inhibiting Fatty Acid Synthase (FASN) with a FASN inhibitor, methods for treating cancer and viral infections with a FASN inhibitor, and compounds and compositions inhibiting FASN.
1. A method of inhibiting Fatty Acid Synthase (FASN) with a FASN inhibitor that binds to the FASN purine-binding cofactor domain, the method comprising contacting cells that express FASN with an inhibitor that binds to the FASN purine-binding cofactor domain.
2. The method of claim 1 , wherein the inhibitor does not bind to the substrate domain.
3. The method of claim 1 , wherein the inhibitor inhibits both acetate and glucose incorporation into total lipids.
4. The method of claim 3 , wherein the inhibitor inhibits both acetate and glucose incorporation into lipids in the HepG2 cell line with an IC 50 value below about 300 nM.
5. The method of claim 1 , wherein the inhibitor possesses a thiophenopyrimidine scaffold.
6. The method of claim 1 , wherein the inhibitor possesses a thieno[2,3-d]pyrimidine scaffold.
7. The method of claim 1 , wherein the compound is (N-(1-benzylpyrrolidin-3-yl)-5,6-dimethylthieno[2,3-d]pyrimidin-4-amine, or a pharmaceutically acceptable salt thereof.
8. A method of inhibiting viral replication in cells expressing FASN, the method comprising contacting the cells with an inhibitor that binds to the FASN purine-binding cofactor domain.
9. The method of claim 8 , wherein the inhibitor does not bind to the substrate domain.
10. The method of claim 8 , wherein the inhibitor inhibits HIV viral replication in a TZM-bl model of HIV replication with an EC 50 value below about 500 nM.
11. The method of claim 8 , wherein inhibition of FASN reduces HV-1 particle production without affecting intracellular Gag production.
12. The method of claim 8 , wherein the inhibitor attenuates HIV replication during a late stage of its replication cycle.
13. The method of claim 8 , wherein nascent HIV-1 virion production is inhibited without reducing HIV-1 protein synthesis.
14. The method of claim 8 , wherein the inhibitor possesses a thiophenopyrimidine scaffold.
15. The method of claim 8 , wherein the inhibitor possesses a thieno[2,3-d]pyrimidine scaffold.
16. The method of claim 8 , wherein the compound is (N-(1-benzylpyrrolidin-3-yl)-5,6-dimethylthieno[2,3-d]pyrimidin-4-amine, or a pharmaceutically acceptable salt thereof.
17. A method of treating a viral infection in a subject, the method comprising administering to the subject in need thereof, a therapeutically effective amount of a FASN inhibitor that binds to the FASN purine-binding cofactor domain.
18. The method of claim 17 , wherein the viral load is reduced.
19. The method of claim 17 , wherein the viral infection is infection by an enveloped virus.
20. The method of claim 17 , wherein the viral infection is infection by a virus selected from the group consisting of human immunodeficiency virus, cytomegalovirus, Dengue, hepatitis B, hepatitis C, Epstein-Barr, influenza virus, respiratory syncytial virus and West Nile virus.
21. The method of claim 17 , wherein the virus is human immunodeficiency virus.
22. The method of claim 17 , wherein lipid dysregulation-based morbidities are reduced.
23. The method of claim 17 , wherein the inhibitor possesses a thiophenopyrimidine scaffold.
24. The method of claim 17 , wherein the inhibitor possesses a thieno[2,3-d]pyrimidine scaffold.
25. The method of claim 17 , wherein the compound is (N-(1-benzylpyrrolidin-3-yl)-5,6-dimethylthieno[2,3-d]pyrimidin-4-amine, or a pharmaceutically acceptable salt thereof.
26. The method of claim 17 , further comprising co-administration of an additional anti-retroviral compound.