GSK837149A

Description

A number of tumor cells and cell lines have been observed to have highly upregulated expression and activity of fatty acid synthase (FASN). GSK837149A is a selective, reversible inhibitor of FASN (pIC₅₀ = 7.8). It acts by inhibiting the β-ketoacyl reductase activity of FASN.

Biochem/physiol Actions

GSK837149A is the first selective inhibitor of human fatty acid synthase (FAS) known to act specifically and selectively on the KR activity of the enzyme. It was first isolated as a minor impurity in a sample found to be active against the enzyme in a high-throughput screening campaign. This compound and its analogs synthesized, all being symmetrical structures containing a bisulfonamide urea, act by inhibiting the beta-ketoacyl reductase activity of the enzyme. GSK837149A inhibits FAS in a reversible mode, with a Ki value of approximately 30 nm, and it possibly binds to the enzyme-ketoacyl-ACP complex. Although initial results suggest that cell penetration for these compounds is impaired, they still can be regarded as useful tools with which to probe and explore the beta-ketoacyl reductase active site in FAS, helping in the design of new inhibitors.