Stable analogues of geranylgeranyl diphosphate possessing improved geranylgeranyl versus farnesyl protein transferase inhibitory selectivity

Bioorg Med Chem Lett. 2003 Dec 15;13(24):4405-8. doi: 10.1016/j.bmcl.2003.09.035.

Abstract

Phosphonoacetamido(oxy) groups have proven to be good mimics of the diphosphate portion in geranylgeranyl protein transferase I (GGTase I) inhibitors. The introduction of small alkyl groups (Me, Et) into the diphosphate mimic moiety caused a further decrease in collateral farnesyl protein transferase (FTase) inhibitory activity, thereby improving GGTase I over FTase selectivity.

Publication types

  • Comparative Study

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Diterpenes*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Polyisoprenyl Phosphates / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Diterpenes
  • Enzyme Inhibitors
  • Polyisoprenyl Phosphates
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • p21(ras) farnesyl-protein transferase
  • geranylgeranyl pyrophosphate