Discovery of a new class of protein farnesyltransferase inhibitors in the arylthiophene series.
Screening of the ICSN chemical library led to the discovery of 3-(4-chlorophenyl)-4-cyano-5-thioalkylthiophene 2-carboxylic acids as potent farnesyltransferase inhibitors. Enzymatic kinetic studies showed that this original FTI series belongs to the CaaX competitive inhibitor class. Preliminary SAR studies allowed us to improve the IC50 from 110 to 7.5 nM.
Lethu
Sébastien
S
Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherche de Gif-sur-Yvette, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
Ginisty
Maryon
M
Bosc
Damien
D
Dubois
Joëlle
J
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D013876:Thiophenes; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase