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HSP90 mediates targeted degradation of non-client protein PARP1 for breast ancer reatment

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 chaperone-mediated bromodomain-containing protein 4 (BRD4) degraders (BRD4-CHAMPs), HSP90-mediated targeting of cyclin-dependent kinase 4 and 6 (CDK4/6) chimeras (CDK4/6-HEMTACs), and HSP90 interactome-mediated targeting of glutathione peroxidase 4 (GPX4) chimeras (GPX4-HIM-PROTACs). However, HSP90 ATPase inhibitor was used to design the above molecules, which might cause non-specific 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 non-client protein degradation. Herein, we induced unnatural interactions between poly (ADP-ribose) polymerase-1 (PARP1), a non-client protein of HSP90, and HSP90 by bridging them with a small molecule (DDO3602). DDO3602 effectively induced PARP1 degradation (DC50 = 595.8 nM) by forming an unnatural ternary complex. DDO3602 showed multiple E3 ubiquitinases degradation mechanisms by recruiting HSP90 to PARP1. DDO3602 effectively suppressed tumor growth in the MCF-7 xenograft tumor mouse model, showing a tumor-selective manner. In general, this study demonstrates that DDO3602 can degrade the HSP90 non-client protein PARP1 through the ubiquitin-proteasome pathway and exhibits tumor-selective pharmacokinetics.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lei Wang

PROVIDER: PXD065936 | iProX | Wed Jul 09 00:00:00 BST 2025

REPOSITORIES: iProX

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