Discovery and SAR of methylated tetrahydropyranyl derivatives as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT)

J Med Chem. 2011 Jul 28;54(14):5031-47. doi: 10.1021/jm200249a. Epub 2011 Jun 28.


A series of tetrahydropyranyl (THP) derivatives has been developed as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT) for use as anticancer agents. Structural modification of the submicromolar hit compound 3 led to the potent 3-methoxy substituted analogue 27. Further SAR development around the THP ring resulted in an additional 10-fold increase in potency, exemplified by analogue 75 with an IC(50) of 1.3 nM. Active and potent compounds demonstrated a dose-dependent increase in Ras cytosolic protein. Potent ICMT inhibitors also reduced cell viability in several cancer cell lines with growth inhibition (GI(50)) values ranging from 0.3 to >100 μM. However, none of the cellular effects observed using ICMT inhibitors were as pronounced as those resulting from a farnesyltransferase inhibitor.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / drug effects
  • Cytosol / metabolism
  • Drug Screening Assays, Antitumor
  • Gene Knockout Techniques
  • Humans
  • Protein Methyltransferases / antagonists & inhibitors*
  • Protein Methyltransferases / genetics
  • Pyrans / chemical synthesis*
  • Pyrans / chemistry
  • Pyrans / pharmacology
  • Recombinant Proteins / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • ras Proteins / biosynthesis


  • Antineoplastic Agents
  • Pyrans
  • Recombinant Proteins
  • Protein Methyltransferases
  • protein-S-isoprenylcysteine O-methyltransferase
  • ras Proteins