HSP90 Mediates Targeted Degradation of Nonclient Protein PARP1 for Breast Cancer Treatment

作者：Wei Liu, Jianfeng Liu, Huangliang Shu, Lixiao Zhang, Xingyu Yin, Xiaoli Xu, Qidong You, Lei Wang · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00409 · 被引用次数：10 · 研究领域：Protein Degradation and Inhibitors、Advancements in Semiconductor Devices and Circuit Design、PARP inhibition in cancer therapy

Abstract Heat shock protein 90 (HSP90) has been developed as an effector in mediating targeted protein degradation (TPD), representing a novel strategy in TPD drug design. The majority of reported cases of HSP90-mediated degradation targeted HSP90 client proteins, including BRD4-CHAMPs, CDK4/6-HEMTACs, and GPX4-HIM-PROTACs. However, HSP90 ATPase inhibitor was used to design the above molecules, which might cause nonspecific degradation of other client proteins. In this study, we sought to broaden the scope of HSP90-mediated proteolysis-targeting chimeras (HSPTACs) from client protein degradation to include nonclient protein degradation. Herein, we induced unnatural interactions between poly(ADP-ribose) polymerase-1 (PARP1), a nonclient protein of HSP90, and HSP90 by bridging them with a small molecule (DDO3602). DDO3602 effectively induced PARP1 degradation through a multi-E3 ubiquitin ligase-mediated degradation pathway. In general, this study demonstrates that DDO3602 can degrade the HSP90 nonclient protein PARP1 through the ubiquitin-proteasome pathway and exhibits tumor-selective pharmacokinetics.