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

Bioorg Med Chem Lett. 2011 May 1;21(9):2616-20. doi: 10.1016/j.bmcl.2011.01.078. Epub 2011 Jan 22.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Cysteine / analogs & derivatives*
  • Cysteine / chemical synthesis
  • Cysteine / chemistry
  • Cysteine / pharmacology
  • Enzyme Activation / drug effects*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Protein Methyltransferases / antagonists & inhibitors*
  • Protein Processing, Post-Translational

Substances

  • Enzyme Inhibitors
  • S-farnesylcysteine
  • Protein Methyltransferases
  • protein-S-isoprenylcysteine O-methyltransferase
  • Cysteine