title: Lipid and sulfur substituted prenylcysteine analogs as human Icmt inhibitors.
abstract: Inhibition of isoprenylcysteine carboxyl methyltransferase (Icmt) offers a promising strategy for K-Ras driven cancers. We describe the synthesis and inhibitory activity of substrate-based analogs derived from several novel scaffolds. Modifications of both the prenyl group and thioether of N-acetyl-S-farnesyl-L-cysteine (AFC), a substrate for human Icmt (hIcmt), have resulted in low micromolar inhibitors of Icmt and have given insights into the nature of the prenyl binding site of hIcmt.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Bergman
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: D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D015394:Molecular Structure; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D008055:Lipids; C542732:prenylcysteine; D013455:Sulfur; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D003545:Cysteine