热休克蛋白 90 (Hsp90) 和拓扑异构酶 IIα (TopoIIα) 是 GHKL 蛋白超家族的成员，两者都具有经过临床验证的抗癌药物靶点作用。我们报告发现了第一类针对 TopoIIα 的 ATP 结合位点和 Hsp90 C 末端结构域的双重抑制剂，在体外和体内均显示出有效的癌症生长抑制作用。最初，一种已知的 TopoIIα 抑制剂化合物 3 被证明能够与 Hsp90 的 C 端结构域结合，但不与其 ATP 结合 N 端结构域结合。然后制备并评估了 19 个类似物以研究结构-活性关系，其中几种在体外抑制 SK-N-MC 尤文肉瘤细胞的生长。化合物 3 成为最有效的生长抑制剂之一 (IC50 = 0.33 ± 0.04 µM)，证明能够在体外诱导 SK-N-MC 细胞凋亡和细胞周期停滞，并在体内减缓尤文肉瘤的生长在斑马鱼模型中。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Heat shock protein 90 (Hsp90) and topoisomerase IIα (TopoIIα) are members of the GHKL protein superfamily, both with clinically validated roles as anticancer drug targets. We report the discovery of the first class of dual inhibitors targeting the ATP-binding site of TopoIIα and the C-terminal domain of Hsp90, displaying potent cancer growth inhibition both in vitro and in vivo. Initially, a known TopoIIα inhibitor, compound 3, was shown to bind to the C-terminal domain of Hsp90, but not to its ATP-binding N-terminal domain. Nineteen analogs were then prepared and evaluated to investigate the structure-activity relationships, several of which inhibited the growth of SK-N-MC Ewing sarcoma cells in vitro. Compound 3 emerged as one of the most potent growth inhibitors (IC50 = 0.33 ± 0.04 µM), demonstrating the ability to induce apoptosis and cell cycle arrest in SK-N-MC cells in vitro, and to slow the growth of Ewing sarcoma in vivo in a zebrafish model.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.