Identification of a class of novel tubulin inhibitors

Xin Yi, Bo Zhong, Kerri M. Smith, Werner J. Geldenhuys, Ye Feng, John J. Pink, Afshin Dowlati, Yan Xu, Aimin Zhou, Bin Su

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

We previously developed a series of anticancer agents based on cyclooxygenase-2 (COX-2) inhibitor nimesulide as a lead compound. However, the molecular targets of these agents still remain unclear. In this study, we synthesized a biotinylated probe based on a representative molecule of the compound library and performed protein pull-down assays to purify the anticancer targets of the compound. Via proteomic approaches, the major proteins bound to the probe were identified to be tubulin and heat shock protein 27 (Hsp27), and the compound inhibited tubulin polymerization by binding at the colchicine domain. However, the tubulin inhibitory effect of the compound activated the Hsp27 phosphorylation and possibly overrode the direct Hsp27 inhibitory effects, which made it difficult to solely validate the Hsp27 target. Taken together, the compound was a dual ligand of tubulin and Hsp27, inhibited tubulin polymerization, and had the potential to be a class of new chemotherapeutic agents.

Original languageEnglish (US)
Pages (from-to)3425-3435
Number of pages11
JournalJournal of Medicinal Chemistry
Volume55
Issue number7
DOIs
StatePublished - Apr 12 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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