Identification of a class of novel tubulin inhibitors

J Med Chem. 2012 Apr 12;55(7):3425-35. doi: 10.1021/jm300100d. Epub 2012 Apr 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzodioxoles / chemistry
  • Benzodioxoles / pharmacology*
  • Biotinylation
  • Cell Line, Tumor
  • HSP27 Heat-Shock Proteins / antagonists & inhibitors
  • HSP27 Heat-Shock Proteins / metabolism
  • Humans
  • Models, Molecular
  • Molecular Probes / chemistry
  • Phosphorylation
  • Protein Binding
  • Proteomics
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Tubulin / metabolism
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology*


  • Antineoplastic Agents
  • Benzodioxoles
  • HSP27 Heat-Shock Proteins
  • Molecular Probes
  • Sulfonamides
  • Tubulin
  • Tubulin Modulators
  • benzo(1,3)dioxole-5-carboxylic acid (3-(2,5-dimethylbenzyloxy)-4-(methanesulfonylmethylamino)phenyl)amide