A novel class of highly potent, selective, and non-peptidic inhibitor of Ras farnesyltransferase (FTase)

Bioorg Med Chem Lett. 2001 Dec 3;11(23):3069-72. doi: 10.1016/s0960-894x(01)00624-2.

Abstract

Design, synthesis and structure-activity relationship of a class of aryl pyrroles as farnesyltransferase inhibitors are described. In vitro and in vivo evaluation of a panel of these inhibitors led to identification of 2 (LB42908) as a highly potent (IC(50)=0.9 nM against H-Ras and 2.4 nM against K-Ras) antitumor agent that is currently undergoing preclinical studies.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology*
  • Inhibitory Concentration 50
  • Mice
  • Mice, Nude
  • Peptides / chemistry
  • Piperazines / chemistry*
  • Piperazines / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Imidazoles
  • LB42908
  • Peptides
  • Piperazines
  • Alkyl and Aryl Transferases
  • p21(ras) farnesyl-protein transferase