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

Previously, vibsanin B (ViB) was found to preferentially target HSP90 beta compared to HSP90 alpha. In this study, multiple experiments, including pull-down assays of biotin-ViB with recombinant HSP90 beta-NTD, MD, CTD, and full-length HSP90 beta, molecular docking of ViB and its derivatives to the HSP90 CTD, and a inhibition assay of interaction of the HSP90 beta 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 mu M 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.