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

Dora Carrico, Michelle A. Blaskovich, Cynthia J. Bucher, Saïd M. Sebti, Andrew Hamilton

Research output: Contribution to journalArticle

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 IC 50 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.

Original languageEnglish (US)
Pages (from-to)677-688
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number3
DOIs
StatePublished - Feb 1 2005

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Scaffolds
geranylgeranyltransferase type-I
Peptidomimetics
Dipeptides
Phenylalanine
Antineoplastic Agents
Enzymes
p21(ras) farnesyl-protein transferase

Keywords

  • Antitumor agents
  • Farnesyltransferase
  • Geranylgeranyltransferase-I
  • Peptidomimetics

ASJC Scopus subject areas

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

Cite this

Design, synthesis, and evaluation of potent and selective benzoyleneurea-based inhibitors of protein geranylgeranyltransferase-I. / Carrico, Dora; Blaskovich, Michelle A.; Bucher, Cynthia J.; Sebti, Saïd M.; Hamilton, Andrew.

In: Bioorganic and Medicinal Chemistry, Vol. 13, No. 3, 01.02.2005, p. 677-688.

Research output: Contribution to journalArticle

Carrico, Dora ; Blaskovich, Michelle A. ; Bucher, Cynthia J. ; Sebti, Saïd M. ; Hamilton, Andrew. / Design, synthesis, and evaluation of potent and selective benzoyleneurea-based inhibitors of protein geranylgeranyltransferase-I. In: Bioorganic and Medicinal Chemistry. 2005 ; Vol. 13, No. 3. pp. 677-688.
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