Design, synthesis and early structure-activity relationship of farnesyltransferase inhibitors which mimic both the peptidic and the prenylic substrate

Inhibition of the farnesylation of ras proteins has been identified as a pr omising target in tumor therapy. Only a few farnesyltransferase inhibitors are bisubstrate analogues displaying features of both substrates, the farne sylpyrophosphate and the C-terminal CAAX-tetrapeptide sequence of the res p rotein. These known bisubstrate analogues consist of an AAX-tripeptide and a farnesyl residue connected through various linkers. We have developed a c lass of novel compounds that mimic a bisubstrate inhibitor structure and th at differ from the known ones by lacking peptidic or farnesylic substructur es. Long chain fatty acids and aryl-substituted carboxylic acids were used as farnesyl surrogates. These structures were linked to isoleucine amide, b enzoic acid amide, N-substituted aminobenzenesulfonamides and N-alpha-aryl- substituted methionine derivatives, respectively, which function as AA- or AAX-mimetics. (C) 2000 Elsevier Science Ltd. All rights reserved.