tailieunhanh - Báo cáo khoa học: Discovery of GSK837149A, an inhibitor of human fatty acid synthase targeting the b-ketoacyl reductase reaction

GSK837149A has been identified as a selective inhibitor of human fatty acid synthase (FAS). The compound was first isolated as a minor impurity in a sample found to be active against the enzyme in a high-throughput screening campaign. | ễFEBS Journal Discovery of GSK837149A an inhibitor of human fatty acid synthase targeting the b-ketoacyl reductase reaction Maria Jesus Vazquez1 William Leavens2 Ronggang Liu3 Beatriz Rodríguez1 Martin Read2 Stephen Richards2 Deborah Winegar4 and Juan Manuel Dominguez1 1 GlaxoSmithKline R D BiologicalReagents and Assay Development Department Centro de Investigacion Basica Tres Cantos Spain 2 GlaxoSmithKline R D AnalyticalChemistry Department Medicines Research Center Stevenage UK 3 GlaxoSmithKline R D Cardiovascular and UrogenitalCentre of Excellence for Drug Discovery King of Prussia PA USA 4 GlaxoSmithKline R D Metabolic Centre of Excellence for Drug Discovery Research Triangle Park Durham NC USA Keywords breast cancer fatty acid synthase GSK837149A ketoacyl reductase obesity Correspondence J. M. Dominguez GlaxoSmithKline R D Centro de Investigacion Basica C Santiago Grisolia 4 28760-Tres Cantos Spain Fax 34 91 807 4062 Tel 34 91 807 4000 E-mail Received 28 November 2007 revised 21 January 2008 accepted 30 January 2008 doi GSK837149A has been identified as a selective inhibitor of human fatty acid synthase FAS . The compound was first isolated as a minor impurity in a sample found to be active against the enzyme in a high-throughput screening campaign. The structure of this compound was confirmed by NMR and MS studies and evaluation of the newly synthesized molecule confirmed its activity against FAS. The compound and other analogs synthesized all being symmetrical structures containing a bisulfonamide urea act by inhibiting the b-ketoacyl reductase activity of the enzyme. GSK837149A inhibits FAS in a reversible mode with a Ki value of 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 b-ketoacyl reductase active site in FAS .