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 (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.