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

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 (<b>DDO3602</b>). <b>DDO3602</b> effectively induced PARP1 degradation through a multi-E3 ubiquitin ligase-mediated degradation pathway. In general, this study demonstrates that <b>DDO3602</b> can degrade the HSP90 nonclient protein PARP1 through the ubiquitin-proteasome pathway and exhibits tumor-selective pharmacokinetics.