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 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.

中文翻译：

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Vibsanin B衍生物的设计，合成和生物活性：新型的HSP90 C末端抑制剂

以前，发现Vibsanin B（ViB）比HSP90α优先靶向HSP90β。在这项研究中，进行了多个实验，包括使用重组HSP90β-NTD，MD，CTD和全长HSP90β进行生物素-ViB的下拉测定，ViB及其衍生物与HSP90 CTD的分子对接以及相互作用的抑制测定ViB衍生物对带有GST标签的亲环蛋白40（Cyp40）的HSP90βCTD的研究表明，ViB可以直接与HSP90 C末端结合。根据对接预测和一级结构-活性关系（SAR），设计并化学合成了一系列着眼于C18位置的ViB类似物，以及衍生自C4，C7和C8位置的化合物。化合物12f（IC ₅₀相对于SK-BR-3 = 1.12μM）具有强大的药物样特性。总的来说，我们的研究结果表明，与vibsanin乙支架的化合物是一类新的HSP90的C -有相当大的潜力作为抗癌剂终端抑制剂。