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 (IC 50 = 170 nM). These PGGTase-I inhibitors represent novel and promising leads for the development of potent inhibitors of mammalian PGGTase-I as antitumor agents. A series of novel protein geranylgeranyltransferase-I (PGGTase-I) inhibitors based on a benzoyleneurea scaffold has been synthesized. Using a benzoyleneurea scaffold as a mimetic for the central dipeptide (AA), we have developed CAAX peptidomimetic inhibitors that selectively block the activity of PGGTase-I over the closely related enzyme protein farnesyltransferase. In this new class of PGGTase-I inhibitors, compound ( 6c) with X = L-phenylalanine, displayed the highest inhibition activity against PGGTase-I with an IC 50 value of 170 nM. The inhibitors described in this study represent novel and promising leads for the development of potent and selective inhibitors of mammalian PGGTase-I for potential application as antitumor agents.