Design, synthesis, and evaluation of potent and selective benzoyleneurea-based inhibitors of protein geranylgeranyltransferase-I

Bioorg Med Chem. 2005 Feb 1;13(3):677-88. doi: 10.1016/j.bmc.2004.10.053.

Abstract

A series of novel protein geranylgeranyltransferase-I (PGGTase-I) inhibitors based on a benzoyleneurea scaffold has been synthesized. Using a benzoyleneurea scaffold as a mimetic for the central dipeptide (AA), we have developed CAAX peptidomimetic inhibitors that selectively block the activity of PGGTase-I over the closely related enzyme protein farnesyltransferase. In this new class of PGGTase-I inhibitors, compound (6c) with X=L-phenylalanine, displayed the highest inhibition activity against PGGTase-I with an IC50 value of 170 nM. The inhibitors described in this study represent novel and promising leads for the development of potent and selective inhibitors of mammalian PGGTase-I for potential application as antitumor agents.

Publication types

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

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Animals
  • Drug Design*
  • Enzyme Inhibitors / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry / methods
  • Models, Molecular
  • Molecular Structure
  • Urea / chemistry*
  • Urea / pharmacology*

Substances

  • Enzyme Inhibitors
  • Urea
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I