New antitumor leads from a peptidomimetic library

László Õrfi, Frigyes Wáczek, István Kövesdi, György Mészáros, Miklós Idei, Anikó Horváth, Ferenc Hollósy, Marianna Mák, Zsolt Szegedi, Béla Szende, György Kéri

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

A parallel combinatorial library of over 1600 compounds has been designed and synthesized for the development of new potential peptidomimetic protein tyrosine kinase (PTK) inhibitor leads. These peptidomimetic molecules are aimed at intervening with the substrate binding site of the pp60(c-src) enzyme. The new structures were based on known PTK inhibitors with at least two variously substituted aromatic moieties attached by spacer groups of different length and flexibility. Eleven bis-aryl-type inhibitory compounds were found in the range of 18-100 μM IC50 concentrations from combinations of 12 different substituents. Molecular modeling of the active compounds showed a characteristic distance of 12-14 Å between the farthest sp2 carbon atoms of the two aromatic rings. Conformational analysis of several peptide substrates recently found for pp60(c-src) PTK showed that the energy- minimized conformers had the same distance between the two aromatic moieties. Several compounds in the library not only showed remarkable PTK inhibitory activity but also a significant apoptosis-inducing effect on HT-29 human colon tumor cells.

Original languageEnglish
Pages (from-to)325-333
Number of pages9
JournalLetters in Peptide Science
Volume6
Issue number5-6
DOIs
Publication statusPublished - Jan 1 1999

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Keywords

  • Antiproliferative effect
  • Apoptosis
  • Combinatorial library
  • Isosteric structures
  • Oxaniloyl hydrazides
  • Peptidomimetics
  • Substrate-binding site
  • Tyrosine kinase inhibition

ASJC Scopus subject areas

  • Biochemistry

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