Synthesis and Anticancer Mechanism Investigation of Dual Hsp27 and Tubulin Inhibitors

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Journal of Medicinal Chemistry


Heat shock protein 27 (Hsp27) is a chaperone protein, and its expression is increased in response to various stress stimuli including anticancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anticancer drug development.


This research was supported by a startup fund from Cleveland State University and also partially supported by Grant R15AI 103889 (B.S.), Center for Gene Regulation in Health and Disease of CSU, and National Science Foundation Major Research Instrumentation Grants CHE-0923398 and CHE- 1126384. We thank the Developmental Therapeutic Program at the National Cancer Institute for screening the compounds against 60 human cancer cell lines.