Synthesis and Anticancer Mechanism Investigation of Dual Hsp27 and Tubulin Inhibitors
breast-cancer; c-dependent activation; cancer cells; chaperone activity; cytochrome-c; heat-shock proteins; in-vitro; nimesulide analog jcc76; pancreatic-cancer; Pharmacology & Pharmacy; self-association
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.
Zhong B; Chennamaneni S; Lama R; Yi X; Geldenhuys W J; Pink J J; Dowlati A; Xu Y; Zhou A M; Su B
Journal of Medicinal Chemistry
2013
2013-07
Journal Article
<a href="http://doi.org/10.1021/jm4004736" target="_blank" rel="noreferrer noopener">10.1021/jm4004736</a>
Identification of a Class of Novel Tubulin Inhibitors
agents; analog jcc76; biological evaluation; breast-cancer cells; halichondrin-b; heat-shock proteins; hsp27 phosphorylation; in-vivo; nimesulide; nonsteroidal antiinflammatory drugs; Pharmacology & Pharmacy; tumor-cells
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.
Yi X; Zhong B; Smith K M; Geldenhuys W J; Feng Y; Pink J J; Dowlati A; Xu Y; Zhou A M; Su B
Journal of Medicinal Chemistry
2012
2012-04
Journal Article
<a href="http://doi.org/10.1021/jm300100d" target="_blank" rel="noreferrer noopener">10.1021/jm300100d</a>