PXD062839-1

PXD062839 is an original dataset announced via ProteomeXchange.

Title	Elaboration of molecular glues that target TRIM21 into TRIMTACs that degrade protein aggregates
Description	Approaches for the discovery of molecular glues remain limited. Here we report a phenotypic screening approach in which cytotoxins whose mechanisms require ubiquitination show gain of viability following pharmacological inhibition of the Ubiquitin-life modifier activating enzyme (UBA1/UAE). This approach revealed PRLX-93936 and BMS-214662 as molecular glues that directly target the E3 ligase TRIM21 to induce degradation of nucleoporin proteins and inhibit nuclear trafficking. The cytotoxicity of these agents correlates strongly with TRIM21 expression, suggesting re-evaluation of these clinically-tested agents in patients with TRIM21-high cancers. Relative to recently-disclosed TRIM21-targeting glues, PRLX-93936 and newly-synthesized analogs represent a distinct structural series, lack known cellular off-targets, and offer greatly enhanced potency. Additionally, we have elaborated PRLX-93936 to the first ‘TRIMTAC’ that uses wild-type TRIM21 to degrade a multimeric protein. Together our work creates new opportunities for targeted protein degradation and enables the design of additional TRIM21-targeting glues and TRIMTACs.
HostingRepository	PRIDE
AnnounceDate	2025-06-17
AnnouncementXML	Submission_2025-06-17_10:14:34.458.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Belinda Willard
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-11 00:33:53	ID requested
⏵ 1	2025-06-17 10:14:34	announced

Dataset with its publication pending

submitter keyword: nucleoporin,targeted protein degradation, molecular glue degraders, PROTAC

Drew Adams, PhD
contact affiliation	Case Western Reserve University, Department of Genetics and Genome Sciences, School of Medicine
contact email	drew.adams@case.edu
lab head
Belinda Willard
contact affiliation	Cleveland Clinic
contact email	willarb@ccf.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/06/PXD062839

PRIDE project URI

• PRIDE
  1. PXD062839
     1. Label: PRIDE project
     2. Name: Elaboration of molecular glues that target TRIM21 into TRIMTACs that degrade protein aggregates