Structures of FPP-, CAAX-based, and bisubstrate inhibitors of FTase.

(A) Chemical structures of FPP and FPP-based inhibitors of FTase and PPMTase. FPP is composed of a hydrophobic farnesyl group and a highly charged pyrophosphate moiety. The basic structural element in the FTase inhibitors is a farnesyl group, a pyrophosphate isostere, and a linker. (B) CAAX-based FTase inhibitors. Structural comparison between CAAX-based FTase inhibitors of the pseudopeptide class and the CAAX tetrapeptides CIFM and CVFM. The potent, nonsubstrate FTase inhibitors CIFM and CVFM were identified by systematic amino acid replacements within the CAAX sequence. In FTI-276 and FTI-277, the AA residues of the CAAX motif have been replaced by a hydrophobic linker. (C) In bisubstrate FTase inhibitors, the farnesyl group of FPP and the tripeptide group of the CAAX motif are connected via a linker.