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

Anil Vasudevan, Yimin Qian, Andreas Vogt, Michelle A. Blaskovich, Junko Ohkanda, Said M. Sebti, Andrew D. Hamilton

Research output: Contribution to journalArticlepeer-review


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 nonthiol-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.

Original languageEnglish (US)
Pages (from-to)1333-1340
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number8
StatePublished - Apr 22 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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