Identification of a Class of Novel Tubulin Inhibitors

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-04, Vol.55 (7), p.3425-3435
Main Authors: Yi, Xin, Zhong, Bo, Smith, Kerri M, Geldenhuys, Werner J, Feng, Ye, Pink, John J, Dowlati, Afshin, Xu, Yan, Zhou, Aimin, Su, Bin
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm300100d