Probing the isoprenylcysteine carboxyl methyltransferase (Icmt) binding pocket: Sulfonamide modified farnesyl cysteine (SMFC) analogs as Icmt inhibitors

Human isoprenylcysteine carboxyl methyltransferase (hIcmt) is a promising anticancer target as it is important for the post-translational modification of oncogenic Ras proteins. We herein report the synthesis and biochemical activity of 41 farnesyl-cysteine based analogs versus hIcmt. We have demonstrated that the amide linkage of a hIcmt substrate can be replaced by a sulfonamide bond to achieve hIcmt inhibition. The most potent sulfonamide-modified farnesyl cysteine analog was 6ag with an IC50 of 8.8 ± 0.5 μM for hIcmt.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide