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Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Christopher Rose

LAB HEAD: Christopher Michael Rose

PROVIDER: PXD036865 | Pride | 2022-09-22

REPOSITORIES: Pride

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			Action	DRS
	20181011_Lum1_QLEARLS_OBJ39649_Degrader_MD_A01.raw	Raw
	20181011_Lum1_QLEARLS_OBJ39649_Degrader_MD_A02.raw	Raw
	20181011_Lum1_QLEARLS_OBJ39649_Degrader_MD_A03.raw	Raw
	20181011_Lum1_QLEARLS_OBJ39649_Degrader_MD_A04.raw	Raw
	20181011_Lum1_QLEARLS_OBJ39649_Degrader_MD_A05.raw	Raw

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Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers

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