Discovery of GSK837149A, an inhibitor of human fatty acid synthase targeting the beta-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. 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 beta-ketoacyl reductase activity of the enzyme. GSK837149A inhibits FAS in a reversible mode, with a K(i) 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.
Vázquez
María Jesús
MJ
 GlaxoSmithKline R&D, Biological Reagents and Assay Development Department, Centro de Investigación Básica, Tres Cantos, Spain.
Leavens
William
W
 GlaxoSmithKline R&D, Analytical Chemistry Department, Medicines Research Center, Stevenage, UK.
Liu
Ronggang
R
 GlaxoSmithKline R&D, Cardiovascular and Urogenital Centre of Excellence for Drug Discovery, King of Prussia, PA, USA.
Rodríguez
Beatriz
B
 GlaxoSmithKline R&D, Biological Reagents and Assay Development Department, Centro de Investigación Básica, Tres Cantos, Spain.
Read
Martin
M
 GlaxoSmithKline R&D, Analytical Chemistry Department, Medicines Research Center, Stevenage, UK.
Richards
Stephen
S
 GlaxoSmithKline R&D, Analytical Chemistry Department, Medicines Research Center, Stevenage, UK.
Winegar
Deborah
D
 GlaxoSmithKline R&D, Metabolic Centre of Excellence for Drug Discovery, Research Triangle Park, Durham, NC, USA.
Domínguez
Juan Manuel
JM
 GlaxoSmithKline R&D, Biological Reagents and Assay Development Department, Centro de Investigación Básica, Tres Cantos, Spain.
D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D002853:Chromatography, Liquid; D016503:Drug Delivery Systems; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
D004791:Enzyme Inhibitors; C529260:GSK837149A; D013449:Sulfonamides; D000429:Alcohol Oxidoreductases; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D064429:Fatty Acid Synthases