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: Joel A Bergman, Kalub Hahne, Christine A Hrycyna, Richard A Gibbs
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 18 Pg. 5616-9 (Sep 15 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21782433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Lipids
• prenylcysteine
• Sulfur
• Protein Methyltransferases
• protein-S-isoprenylcysteine O-methyltransferase
• Cysteine

Topics

• Cysteine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Lipids (chemistry)
• Molecular Structure
• Protein Methyltransferases (antagonists & inhibitors, metabolism)
• Stereoisomerism
• Structure-Activity Relationship
• Sulfur (chemistry)