Background:

IC50: 7.7 nM

GSK 2194069 is a potent human fatty acid synthase inhibitor.

Human fatty acid synthase (hFAS) is a multifunctional enzyme solely responsible for the de novo synthesis of long chain fatty acids. hFAS is expressed highly in a number of cancers, while with low observed expression in most normal tissues. Though normal tissues get fatty acids from the diet, tumor tissues can rely on de novo fatty acid synthesis, which makes hFAS an attractive metabolic target for cancer treatment.

In vitro: GSK2194069 displayed acceptable solubility and permeability and thus was chosen for further characterization. GSK2194069 had an IC50 of 29 ± 3.2 nM versus hFAS with acetoacetyl-CoA as the substrate but showed little or no inhibition with crotonyl-CoA andβ-hydroxybutyryl-CoA. GSK2194069 was also found not to inhibit the partial activities of the KS domain [1].

In vivo: In those mice dosed with GSK2194069, tumour growth was inhibited. There was no significant weight loss in the GSK2194069 treated group and no adverse effects were observed. The effect of GSK2194069 in decreasing acetate uptake was demonstrated by scintillation detection of C42b xenograft tumours by 56% 2 hours after dosing with GSK2194069. Inhibition of FAS caused by GSK2194069 led to a decrease in acetate signal in all animals [1].

Clinical trial: N/A

参考文献:
[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, Pagese208–e209