Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125, Modena, Italy.
Department of Chemistry, University of Milano, Via Golgi 19, 20133, Milano, Italy.
ChemistryOpen. 2021 Dec;10(12):1177-1185. doi: 10.1002/open.202100131. Epub 2021 Oct 11.
The design of multi-target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B-Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP-binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B-Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B-Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90-B-Raf-PDHK1 multi-target activities. The designed compounds were synthesized and experimentally validated in vitro. According to the in vitro assays, compounds 4 a, 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi-target activity.
多靶标配体的设计已成为鉴定针对复杂疾病（如癌症）的有效治疗方法的创新方法。最近的研究表明，Hsp90 和 B-Raf 的联合抑制对几种类型的癌症具有协同作用。此外，据报道，PDHK1 具有与 Hsp90 相似的 ATP 结合口袋，在肿瘤起始、维持和进展中发挥重要作用，也参与 B-Raf 致癌蛋白诱导的衰老过程。基于这些前提，同时抑制这些靶标可能为癌症治疗提供多种益处。在这项工作中，我们建立了一种设计策略，包括组装和集成已知对 Hsp90、PDHK1 和 B-Raf 靶标结合重要的分子片段，并通过分子对接选择一组可能具有 Hsp90-B-Raf-PDHK1 多靶标活性的化合物。设计的化合物已被合成并在体外进行了实验验证。根据体外测定，化合物 4a、4d 和 4e 强烈抑制 Hsp90 并适度抑制 PDHK1 激酶。最后，进行了分子动力学模拟，以提供对其多靶标活性结构基础的进一步了解。
