Identification of a novel nanomolar inhibitor of hIcmt via a carboxylate replacement approach?

MedChemComm Pub Date: 2012-08-03 DOI: 10.1039/C2MD20108A

Abstract

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 IC50 value of 860 nM and cellular effects consistent with hIcmt inhibition.

Graphical abstract: Identification of a novel nanomolar inhibitor of hIcmt via a carboxylate replacement approach
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