Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold

J. Ohkanda, J. W. Lockman, M. A. Kothare, Y. Qian, M. A. Blaskovich, S. M. Sebti, A. D. Hamilton

Research output: Contribution to journalArticle

Abstract

By modification of key carboxylate, hydrophobic, and zinc-binding groups projected from a sterically restricted terphenyl scaffold, a series of simple and nonpeptide mimetics of the CysVal-Ile-Met tetrapeptide substrate of protein farnesyltransferase (FTase) have been designed and synthesized. A crystal structure of 4-nitro-2-phenyl-3′-methoxycarbonylbiphenyl shows that the triphenyl fragment provides a large hydrophobic surface that potentially mimics the hydrophobic side chains of the three terminal residues in the tetrapeptide. 2-Phenyl-3-(N-(1-(4-cyanobenzyl)-1H-imidazol-5-yl)methyl)amino- 3′carboxylbiphenyl, in which the free thiol group was replaced with a 1-(4-cyanobenzyl)imidazole group, shows submicromolar inhibition activity against FTase in vitro and inhibits H-Ras processing in whole cells.

Original languageEnglish (US)
Pages (from-to)177-188
Number of pages12
JournalJournal of Medicinal Chemistry
Volume45
Issue number1
DOIs
StatePublished - Jan 3 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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