Design, synthesis, and evaluation of potent and selective benzoyleneurea-based inhibitors of protein geranylgeranyltransferase-I

Using a benzoyleneurea scaffold as a mimetic for the central dipeptide (AA), CAAX peptidomimetic inhibitors that selectively block the activity of PGGTase-I over PFTase were synthesized. In this series, compound 6c containing a L-phenylalanine moiety displayed the highest inhibition activity against PGGTase-I (IC50 = 170 nM). These PGGTase-I inhibitors represent novel and promising leads for the development of potent inhibitors of mammalian PGGTase-I as antitumor agents.