GSK2194069

IC50: 7.7 nM.

GSK 2194069 is a potent human fatty acid synthase inhibitor.

Human fatty acid synthase (hFAS) is a multifunctional enzyme that catalyzes the de novo synthesis of long-chain fatty acids. In many cancers, hFAS is highly expressed, whereas its expression level is low in most normal tissues. Normal tissues generally obtain fatty acids through diet, while tumor tissues can rely on de novo fatty acid synthesis; therefore, hFAS is expected to be an important metabolic target for cancer therapy.

In vitro: GSK2194069 has acceptable solubility and permeability and was therefore selected for further characterization. Using acetoacetyl-CoA as the substrate, GSK 2194069 has an IC50 value against hFAS of 29 ± 3.2 nM, but shows almost no inhibitory activity when crotonyl-CoA and β-hydroxybutyryl-CoA are used as substrates. In addition, GSK2194069 does not inhibit the partial activity of the KS domain [1].

In vivo: After administration of GSK2194069 to mice, tumor growth was inhibited. In the GSK2194069 treatment group, no significant body weight loss or any side effects were observed. In C42b xenograft tumors, administration of GSK2194069 and testing at 2 hours post-dose showed that GSK2194069 reduced acetate uptake (56%). In all animals, GSK2194069 caused FAS inhibition, thereby reducing the acetate signal [1].

Clinical trials: N/A.

References:
[1] Hardwicke MA, Rendina AR, Williams SP, Moore ML, Wang L, Krueger JA, Plant RN, Totoritis RD, Zhang G, Briand J, Burkhart WA, Brown KK, Parrish CA.? A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site. Nat Chem Biol. 2014 Sep;10(9):774-9.
[2] Greg Shaw, David Lewis, Joan Boren, Antonio Ramos-Montoya, Robert Bielik, Dmitry Soloviev, Brindle Kevin, Neal David.? 509 THERAPEUTIC FATTY ACID SYNTHASE INHIBITION IN PROSTATE CANCER AND THE USE OF 11C-ACETATE TO MONITOR THERAPEUTIC EFFECTS. The Journal of Urology. 2013Volume 189, Issue 4, Supplement, Pages e208–e209.