Probing the hydrophobic pocket of farnesyltransferase

Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors

Yimin Qian, Juan Jose Marugan, Renae D. Fossum, Andreas Vogt, Said M. Sebti, Andrew Hamilton

Research output: Contribution to journalArticle

Abstract

Cysteine farnesylation at the carboxylate terminal tetrapeptide CAAX of Ras protein is catalyzed by farnesyltransferase. This lipid modification is necessary for regulatory function of both normal and oncogenic Ras. The high frequency of Ras mutation in human cancers has prompted an intensive study on finding ways of controlling oncogenic Ras function. Inhibition of farnesyltransferase is among the most sought after targets for cancer chemotherapy. We report here the design, synthesis and biological characterization of a series of peptidomimetics as farnesyltransferase inhibitors. These compounds are extremely potent towards farnesyltransferase with IC50 values ranging from subnanomolar to low nanomolar concentrations. They have a high selectivity for farnesyltransferase over the closely related geranylgeranyltransferase-I. Structure-activity relationship studies demonstrated that a properly positioned hydrophobic group significantly enhanced inhibition potency, reflecting an improved complementarity to the large hydrophobic pocket in the CAAX binding site. Copyright (C) 1999 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)3011-3024
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume7
Issue number12
DOIs
StatePublished - Dec 1999

Fingerprint

Farnesyltranstransferase
Peptidomimetics
Substitution reactions
Prenylation
ras Proteins
Chemotherapy
Mutation Rate
Structure-Activity Relationship
Inhibitory Concentration 50
Cysteine
Neoplasms
Binding Sites
Lipids
Drug Therapy

Keywords

  • Anticancer targets
  • Farnesyltransferase inhibitors
  • Hydrophobic pocket
  • Peptidomimetics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Probing the hydrophobic pocket of farnesyltransferase : Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. / Qian, Yimin; Marugan, Juan Jose; Fossum, Renae D.; Vogt, Andreas; Sebti, Said M.; Hamilton, Andrew.

In: Bioorganic and Medicinal Chemistry, Vol. 7, No. 12, 12.1999, p. 3011-3024.

Research output: Contribution to journalArticle

Qian, Yimin ; Marugan, Juan Jose ; Fossum, Renae D. ; Vogt, Andreas ; Sebti, Said M. ; Hamilton, Andrew. / Probing the hydrophobic pocket of farnesyltransferase : Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. In: Bioorganic and Medicinal Chemistry. 1999 ; Vol. 7, No. 12. pp. 3011-3024.
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