Identification of a novel nanomolar inhibitor of hIcmt via a carboxylate replacement approachElectronic supplementary information (ESI) available. See DOI: 10.1039/c2md20108a

A substrate-based approach to human isoprenylcysteine carboxyl methyltransferase (hIcmt) inhibitors via systematic modulation of both the amide and the prenyl regions of N -acetyl- S -farnesyl- l -cysteine (AFC) led to potent inhibitors of this promising anti-cancer target. However, to date, molecules containing changes to the important carboxylate pharmacophore have not been extensively explored as Icmt inhibitors. We synthesized a set of 39 analogs in which the carboxylate region was chemically redefined using a farnesyl thiopropionic acid (FTPA) backbone. Herein, we demonstrated that modifications of carboxylate motif can lead to potent, sub-micromolar inhibitor of the enzyme. Our most potent inhibitor, analog 12 , demonstrated an in vitro IC 50 value of 860 nM and cellular effects consistent with hIcmt inhibition. Replacement of the carboxylate moiety in FTA led to 12 , a potent hlcmt inhibitor (IC 50 = 860 nm).