title: Probing the isoprenylcysteine carboxyl methyltransferase (Icmt) binding pocket: sulfonamide modified farnesyl cysteine (SMFC) analogs as Icmt inhibitors.
abstract: 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 IC(50) of 8.8±0.5 μM for hIcmt.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Jaimeen D
authors.initials: JD
authors.lastname: Majmudar
authors.forename: Kalub
authors.initials: K
authors.lastname: Hahne
authors.forename: Christine A
authors.initials: CA
authors.lastname: Hrycyna
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
mesh_terms: D001665:Binding Sites; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors*; D011499:Protein Processing, Post-Translational
chemical_list: D004791:Enzyme Inhibitors; C057785:S-farnesylcysteine; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D003545:Cysteine