PXD065936

PXD065936 is an original dataset announced via ProteomeXchange.

Title	HSP90 mediates targeted degradation of non-client protein PARP1 for breast ancer reatment
Description	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.
HostingRepository	iProX
AnnounceDate	2025-07-09
AnnouncementXML	Submission_2025-07-09_01:06:22.501.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Wei Liu
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-09 01:05:57	ID requested
⏵ 1	2025-07-09 01:06:22	announced

Dataset with its publication pending

submitter keyword: HSP90-mediated proteolysis-targeting chimeras (HSPTACs), PARP1, DDO-3602

Lei Wang
contact affiliation	China Pharmaceutical University
contact email	leiwang.91@cpu.edu.cn
lab head
Wei Liu
contact affiliation	China Pharmaceutical University
contact email	liuweiyoujihecheng@163.com
dataset submitter

iProX dataset URI