Farnesyltransferase Inhibitors: From Squalene Synthase Inhibitors to the Clinical Agent BMS-214662

Abstract

We have discovered a number of distinct classes of inhibitors of the enzyme farnesyltransferase, an attractive new therapeutic target in oncology. The inhibitor classes include ones that are farnesylpyrophosphate-based, bisubstrates, thiol--and imidazole-based tetrapeptides, imidazole-based dipeptides and ultimately imidazole-based tetrahydrobenzodiazepines. The latter class yielded (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H--imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), which has entered clinical trials.