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Design, Synthesis, and Biological Activities of Vibsanin B Derivatives: A New Class of HSP90 C‑Terminal Inhibitors

By Li-Dong Shao (1393552), Jia Su (128774), Baixin Ye (4531261), Jiang-Xin Liu (4531264), Zhi-Li Zuo (1670434), Yan Li (23143), Yue-Ying Wang (4531267), Chengfeng Xia (266690) and Qin-Shi Zhao (1647877)


Previously, vibsanin B (ViB) was found to preferentially target HSP90β compared to HSP90α. In this study, multiple experiments, including pull-down assays of biotin-ViB with recombinant HSP90β-NTD, MD, CTD, and full-length HSP90β, molecular docking of ViB and its derivatives to the HSP90 CTD, and a inhibition assay of interaction of the HSP90β CTD with GST-tagged cyclophilin 40 (Cyp40) by ViB derivatives, suggest that ViB can directly bind to the HSP90 C-terminus. On the basis of the docking predictions and primary structure–activity relationships (SARs), a series of ViB analogues devised with focus on the C18 position, along with compounds derivatized at the C4, C7, and C8 positions, were designed and chemically synthesized. Compound <b>12f</b> (IC<sub>50</sub> = 1.12 μM against SK-BR-3) exhibits great potency with drug-like properties. Overall, our findings demonstrate that compounds with the vibsanin B scaffold are a new class of HSP90 C<i>-</i>terminal inhibitors with considerable potential as anticancer agents

Topics: Biochemistry, Medicine, Pharmacology, Biotechnology, Ecology, Virology, Space Science, Environmental Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, docking predictions, Compound 12 f, compounds derivatized, HSP 90β CTD, Biological Activities, C 18 position, vibsanin B scaffold, C 8 positions, HSP 90 CTD, GST-tagged cyclophilin 40, 1.12 μ M, HSP 90 C, New Class, SK-BR, HSP 90β-NTD MD, ViB derivatives, Vibsanin B Derivatives, drug-like properties, HSP 90 C-terminus, anticancer agents, SAR, terminal inhibitors, inhibition assay, IC 50, vibsanin B, HSP 90α., ViB analogues, target HSP 90β
Year: 2017
DOI identifier: 10.1021/acs.jmedchem.7b01395.s001
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Provided by: FigShare
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