Fatty acid synthase (FASN) is a central regulator of lipid metabolism. FASN provides the fatty acids needed to sustain tumor growth, as a potential target for human malignant tumors. And it also involves lipid metabolism, glycolysis, and amino acid metabolism. Especially, fatty acids are the energy source of cells and ensure the structural integrity of cell membranes and walls. Previous studies have shown that biologically aggressive tumor subpopulations are constitutionally highly expressive of type I FASN. Clearly, FASN inhibitors show significant antitumor activity. They are effective in the xenotransplantation of breast cancer cells in nude mice. Moreover, FASN is a possible target for obesity. FASN inhibitors reduce food intake and cause weight loss in mice. However, there is currently a lack of FASN inhibitors which is reversible and selective to human enzymes. Here we’ll introduce a selective human FASN inhibitor, GSK837149A.
GSK837149A exerts a selective and reversible inhibition on Human Fatty Acid Synthase (FASN).
Specifically, GSK837149A targets only the KR domain of FASN (β-ketoacyl reductase) instead of DH (dehydratase) or ER (β-enoyl reductase). Certainly, it is selective to type I FASN (Ki=30 nM) without inhibiting FabG (the KR counterpart in type II FASN). Meanwhile, it displays reversible FASN inhibition and rapidly disappears after dilution. Interestingly, GSK837149A (0.1 nM-0.1 mM) is also a competitive inhibitor of NADPH and a non-competitive inhibitor of acetoacetyl-CoA. But it has very low cellular permeability. However, the research of GSK837149A is still in its infancy.
Above all, GSK837149A selectively and reversibly inhibits type I FASN, and exhibits potential inhibition targeting obesity and breast cancer.
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 Singha PK, et al. Eur J Pharm Sci. 2020 Apr 7;149:105321.