PXD036865-1

PXD036865 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-20 14:47:15	ID requested
⏵ 1	2022-09-22 08:59:27	announced

Dataset with its publication pending

submitter keyword: Human, PROTAC, Degrader, TMT, Isobaric Labeling, Proteome, Ubiquityome

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

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PRIDE project URI

• PRIDE
  1. PXD036865
     1. Label: PRIDE project
     2. Name: Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers