Farnesyl Protein Transferase Inhibitors: Medicinal Chemistry, Molecular Mechanisms, and Progress in the Clinic

Over a decade has passed since the first report describing farnesyl protein transferase (FTase)and tetrapeptide inhibitors triggered a search for small-molecule inhibitors that could be developedas oral therapeutics. There are now several farnesyl protein inhibitors (FTIs) in various phases of clinicaldevelopment and at least two compounds have entered phase III. The published data suggest some disappointingactivity in the major solid tumors, with more promising activities emerging from studies of hematologicalmalignancies and glioblastoma. The current compounds emerged from various research strategies includingmodeling around the CAAX motif peptide substrate and the farnesyl pyrophosphate (FPP) substrate, as wellas high-throughput screening campaigns. The interaction of inhibitors in the active site of the FT enzymecan be accurately described thanks to the publication of the X-ray structure as well as excellent mechanisticwork. Published structure–activity data have revealed an interesting convergence on imidazole pharmacophores.The original hypothesis that drove development of FTIs anticipated therapy targeted specifically at thefarnesylated Ras oncoproteins and cancers with ras gene mutations. Asexperience with the newer potent FTIs grew, data emerged to suggest that multiple downstream effectors contributeto the antitumor activity of FTIs. The mechanism(s) of action of FTIs and the full therapeutic activityof the class remain areas of active investigation.