Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase.

A series of imidazole-containing peptidomimetic PFTase inhibitors and their co-crystal structures bound to PFTase and FPP are reported. The structures reveal that the peptidomimetics adopt a similar conformation to that of the extended CVIM tetrapeptide, with the imidazole group coordinating to the catalytic zinc ion. Both mono- and bis-imidazole-containing derivatives, 13 and 16, showed remarkably high enzyme inhibition activity against PFTase in vitro with IC50 values of 0.86 and 1.7 nM, respectively. The peptidomimetics were also highly selective for PFTase over PGGTase-I both in vitro and in intact cells. In addition, peptidomimetics and were found to suppress tumor growth in nude mouse xenograft models with no gross toxicity at a daily dose of 25 mg kg(-1).