Synthesis, pharmacological evaluation, and molecular modeling studies of novel peptidic CAAX analogues as farnesyl-protein-transferase inhibitors

J Med Chem. 2006 Mar 23;49(6):1882-90. doi: 10.1021/jm0506165.


Fifteen analogues of the C-terminal CA1A2X motif were synthesized and evaluated for their inhibition potency against farnesyltransferase (FTase). Replacement of the A2 residue by phenylalanine or tyrosine-derived analogues, in which a different number of methyl groups were introduced on the aromatic ring, resulted in compounds less active than the reference compound CVFM against FTase except for compounds I and VI (IC50=1 microM and 2.5 microM, respectively) that were comparable to CVFM and compound IV (IC50=0.1 microM), which was 6-fold more active than the reference compound. Because pseudopeptidic derivatives I-IX were inactive in the cellular assays, the N-formyl- and methyl-ester derivatives (compounds X-XV) were synthesized and tested on different cell lines, showing, in some cases, activity and appreciable selectivity against transformed cells. To rationalize the obtained results, molecular modeling experiments were carried out suggesting the molecular basis of FTase inhibition by these products.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / analogs & derivatives
  • Alanine / chemical synthesis
  • Alanine / pharmacology
  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Alkyl and Aryl Transferases / chemistry
  • Animals
  • Binding Sites
  • Cell Line
  • Cell Line, Tumor
  • Humans
  • Indoles / chemical synthesis
  • Indoles / pharmacology
  • Mice
  • Models, Molecular*
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / pharmacology
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tyrosine / analogs & derivatives
  • Tyrosine / chemical synthesis
  • Tyrosine / pharmacology


  • Indoles
  • Oligopeptides
  • Tyrosine
  • Alkyl and Aryl Transferases
  • p21(ras) farnesyl-protein transferase
  • Alanine