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PXD046264-1

PXD046264 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleProteolysis Targeting Chimeras With Reduced Off-targets
DescriptionProteolysis 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.
HostingRepositoryPRIDE
AnnounceDate2023-12-20
AnnouncementXMLSubmission_2023-12-20_08:18:39.899.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterEric Fischer
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListiodoacetamide derivatized residue
InstrumenttimsTOF Pro 2
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-10-20 09:55:40ID requested
12023-12-20 08:18:40announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Ubiquitin, CRBN, PROTAC, protein degradation, zinc finger, E3 ligase, off-targets
Contact List
Eric Fischer
contact affiliationDepartment 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 emaileric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliationDana-Farber Cancer Institute
contact emaileric_fischer@dfci.harvard.edu
dataset submitter
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Dataset FTP location
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