PXD068712

PXD068712 is an original dataset announced via ProteomeXchange.

Title	Overcoming Drug Resistance in Chronic Myeloid Leukemia: Rational Development of Druggable Molecular Glue Degraders
Description	Overcoming drug resistance remains a major challenge in targeted therapy. Molecular glue degraders offer a promising solution, but their discovery has been largely serendipitous, limiting systematic development. In this study, we report a rational strategy to convert kinase inhibitors into molecular glue degraders that overcome Bcr-AblT315I-mediated resistance in chronic myeloid leukemia (CML). By engineering the solvent-exposed region of GZD824, we generated a covalent degrader that recruits the previously unexploited E3 ligase UBR4 through covalent engagement of C4512. Structural optimization, which replaced the covalent warhead with a minimal ethyl group, yielded compound 4147. This compound achieved potent Bcr-AblT315I degradation (DC₅₀ = 16.18 nM, Dmax = 91.1%), displayed favorable pharmacokinetics (t1/2 = 4.36 h, F = 69.78%), and demonstrated strong in vivo efficacy (67.8% TGI at 20 mg/kg) with minimal toxicity (≤3% body weight loss), markedly outperforming olverembatinib (26.2% TGI). These findings establish 4147 as a clinically tractable molecular glue degrader to overcome T315I-mediated resistance in CML. More broadly, our design strategy can be applied to other marketed kinase inhibitors, such as imatinib (Gleevec) and ponatinib (Iclusig), through minimal structural modifications that preserve drug-like properties. Beyond its therapeutic implications, this work validates UBR4 as a previously unexploited E3 ligase for targeted protein degradation, thereby expanding the ligase repertoire and providing a general framework for the rational development of druggable molecular glue degraders.
HostingRepository	iProX
AnnounceDate	2026-03-26
AnnouncementXML	Submission_2026-03-26_18:47:43.987.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shengrong Li
SpeciesList	scientific name: Acyrthosiphon pisum; NCBI TaxID: 7029; scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Thermo Fisher Scientific instrument model

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-22 19:32:54	ID requested
⏵ 1	2026-03-26 18:47:44	announced

Dataset with its publication pending

submitter keyword: Molecular Glue Degraders, Bcr-Abl-T315I

Zhengqiu Li
contact affiliation	Jinan University
contact email	pharmlzq@jnu.edu.cn
lab head
Shengrong Li
contact affiliation	Jinan University
contact email	13286803028@163.com
dataset submitter

iProX dataset URI