Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I

J Med Chem. 1999 Apr 22;42(8):1333-40. doi: 10.1021/jm9900873.


The design, synthesis, and biological evaluation of a family of peptidomimetic inhibitors of protein geranylgeranyltransferase-I (PGGTase-I) are reported. The inhibitors are based on the C-terminal CAAL sequence of many geranylgeranylated proteins. Using 2-aryl-4-aminobenzoic acid derivatives as mimetics for the central dipeptide (AA), we have attached a series of imidazole and pyridine derivatives to the N-terminus as cysteine replacements. These non-thiol-containing peptidomimetics show exceptional selectivity for PGGTase-I over the closely related enzyme protein farnesyltransferase (PFTase). This selectivity is retained in whole cells where the inhibitors were shown to block the geranylgeranylation of Rap-1A without affecting the farnesylation of small GTP-binding proteins such as Ras.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Animals
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • GTP-Binding Proteins / biosynthesis
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Leucine / analogs & derivatives*
  • Leucine / chemical synthesis*
  • Leucine / chemistry
  • Leucine / pharmacology
  • Mice
  • Molecular Mimicry
  • Protein Prenylation / drug effects*
  • Structure-Activity Relationship
  • rap GTP-Binding Proteins


  • Enzyme Inhibitors
  • Imidazoles
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • p21(ras) farnesyl-protein transferase
  • GTP-Binding Proteins
  • rap GTP-Binding Proteins
  • Leucine