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Design, Synthesis, and Biological Activities of Vibsanin B Derivatives: A New Class of HSP90 C‑Terminal Inhibitors
journal contribution
posted on 2017-10-11, 00:00 authored by Li-Dong Shao, Jia Su, Baixin Ye, Jiang-Xin Liu, Zhi-Li Zuo, Yan Li, Yue-Ying Wang, Chengfeng Xia, Qin-Shi ZhaoPreviously, 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 12f (IC50 = 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-terminal inhibitors with considerable potential
as anticancer agents.
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docking predictionsCompound 12 fcompounds derivatizedHSP 90β CTDBiological ActivitiesC 18 positionvibsanin B scaffoldC 8 positionsHSP 90 CTDGST-tagged cyclophilin 401.12 μ MHSP 90 CNew ClassSK-BRHSP 90β-NTD MDViB derivativesVibsanin B Derivativesdrug-like propertiesHSP 90 C-terminusanticancer agentsSARterminal inhibitorsinhibition assayIC 50vibsanin BHSP 90α.ViB analoguestarget HSP 90β
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