alpha-Cyanocinnamide derivatives: A new family of non-peptide, non-sulfhydryl inhibitors of Ras farnesylation

Farnesylation of Ras and other proteins is required for their membrane atta chment and normal function. Here we report on the synthesis of alpha-cyanoc innamide derivatives, a new family of farnesyltransferase inhibitors. These compounds are nonpeptidic and do not contain sulfhydryl groups. The most p otent compound is a pure competitive inhibitor with respect to the Ras prot ein and mixed competitive with respect to farnesyl diphosphate. Selectivity studies against geranylgeranyltransferase and biological activities of sel ected compounds are described. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.