Document Report Card

ID: ALA2396529

Journal: J Med Chem

Title: Synthesis and anticancer mechanism investigation of dual Hsp27 and tubulin inhibitors.

Authors: Zhong B, Chennamaneni S, Lama R, Yi X, Geldenhuys WJ, Pink JJ, Dowlati A, Xu Y, Zhou A, Su B.

Abstract: 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.

CiteXplore: 23767669

DOI: 10.1021/jm4004736