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PXD036865 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleSelective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers
DescriptionThe mammalian SWI/SNF helicase SMARCA4 is frequently mutated in cancer and inactivation results in a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving a high degree of SMARCA2 selectivity is likely essential to afford an acceptable therapeutic index and this has been a considerable challenge due to the homology between paralogs. Herein we report the discovery of the first potent and selective SMARCA2 proteolysis-targeting chimera (PROTAC) molecule. Selective degradation was achieved in the absence of selective PROTAC binding and translated to potent in vitro growth inhibition and in vivo efficacy in SMARCA4 mutant models, compared to wild type models. Global ubiquitin mapping and proteome profiling revealed no unexpected off-target degradation. Our study thus highlights the ability to transform a non-selective SMARCA2-binding ligand into a selective and efficacious in vivo SMARCA2 PROTAC, providing a potential therapeutic opportunity for SMARCA4 mutant patients.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterChristopher Rose
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListTMT6plex-126 reporter+balance reagent acylated residue; ubiquitinylated lysine; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Eclipse; Orbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-09-20 14:47:15ID requested
12022-09-22 08:59:27announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Human, PROTAC, Degrader, TMT, Isobaric Labeling, Proteome, Ubiquityome
Contact List
Christopher Michael Rose
contact affiliationDiscovery Proteomics, Genentech
contact emailrose.christopher@gene.com
lab head
Christopher Rose
contact affiliationGenentech
contact emailrose.christopher@gene.com
dataset submitter
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Dataset FTP location
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