PXD036865 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers |
Description | The 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. |
HostingRepository | PRIDE |
AnnounceDate | 2022-09-22 |
AnnouncementXML | Submission_2022-09-22_08:59:27.126.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Christopher Rose |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | TMT6plex-126 reporter+balance reagent acylated residue; ubiquitinylated lysine; monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Orbitrap Eclipse; Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-09-20 14:47:15 | ID requested | |
⏵ 1 | 2022-09-22 08:59:27 | announced | |
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 affiliation | Discovery Proteomics, Genentech |
contact email | rose.christopher@gene.com |
lab head | |
Christopher Rose |
contact affiliation | Genentech |
contact email | rose.christopher@gene.com |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD036865
- Label: PRIDE project
- Name: Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers