Design, synthesis, and characterization of piperazinedione-based dual protein inhibitors for both farnesyltransferase and geranylgeranyltransferase-I

► Various piperazinedione derivatives were designed and synthesized as a new type of peptide mimetic compounds, which were characterized and found to be dual protein inhibitors for both FTase and GGTase-I. ► These compounds have similar chemical and physical properties to -CAAX motif of the protein substrate, which may facilitate their transfer to appropriate drug target in vivo. ► The best inhibitor compound 26b was found to occupy both isoprenoid and peptide substrate binding sites through kinetics and computer molecular docking studies.