PXD046264-1

PXD046264 is an original dataset announced via ProteomeXchange.

Title	Proteolysis Targeting Chimeras With Reduced Off-targets
Description	Proteolysis Targeting Chimeras (PROTACs) are molecules that induce proximity between target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring development of PROTAC design rules that minimize off-target degradation. Here we developed a highthroughput platform that interrogates off-target degradation and found that reported pomalidomide-based PROTACs induce degradation of several ZF proteins. We generated a library of pomalidomide analogs to understand how functionalising different positions of the phthalimide ring, hydrogen bonding, steric and hydrophobic effects impact ZF protein degradation. Modifications of appropriate size on the C5 position reduced off-target ZF degradation, which we validated through target engagement and proteomics studies. By applying these design principles, we developed ALK oncoprotein-targeting PROTACs with enhanced potency and minimal offtarget degradation.
HostingRepository	PRIDE
AnnounceDate	2023-12-20
AnnouncementXML	Submission_2023-12-20_08:18:39.899.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Fischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-20 09:55:40	ID requested
⏵ 1	2023-12-20 08:18:40	announced

Dataset with its publication pending

submitter keyword: Ubiquitin, CRBN, PROTAC, protein degradation, zinc finger, E3 ligase, off-targets

Eric Fischer
contact affiliation	Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
contact email	eric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliation	Dana-Farber Cancer Institute
contact email	eric_fischer@dfci.harvard.edu
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/2023/12/PXD046264

PRIDE project URI

• PRIDE
  1. PXD046264
     1. Label: PRIDE project
     2. Name: Proteolysis Targeting Chimeras With Reduced Off-targets