The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease

J Med Chem. 2005 Aug 25;48(17):5415-8. doi: 10.1021/jm050441z.

Abstract

Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED(50) = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were used for the prediction of the binding modes of the substrate lanosterol and of Tipifarnib, providing a basis for the design of derivatives with selectivity for TcCYP51 over human PFT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Alkyl and Aryl Transferases / chemistry
  • Animals
  • Binding Sites
  • Chagas Disease / drug therapy
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / chemistry
  • Humans
  • Lanosterol / chemistry
  • Models, Molecular
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases / chemistry
  • Protein Binding
  • Quinolones / chemistry*
  • Sterol 14-Demethylase
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemistry*
  • Trypanosoma cruzi / enzymology*

Substances

  • CYP51A1 protein, human
  • Cytochrome P-450 Enzyme Inhibitors
  • Quinolones
  • Trypanocidal Agents
  • Lanosterol
  • Cytochrome P-450 Enzyme System
  • Oxidoreductases
  • Sterol 14-Demethylase
  • Alkyl and Aryl Transferases
  • p21(ras) farnesyl-protein transferase
  • tipifarnib