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

Jennifer Cantley, Xiaofen Ye, Emma Rousseau, Tom Januario, Brian D. Hamman, Christopher M. Rose, Tommy K. Cheung, Trent Hinkle, Leofal Soto, Connor Quinn, Alicia Harbin, Elizabeth Bortolon, Xin Chen, Roy Haskell, Eva Lin, Shang-Fan Yu, Geoff Rosario, Emily Chan, Debra Dunlap, Hartmut Koeppen, Scott Martin, Mark Merchant, Matt Grimmer, Fabio Broccatelli, Jing Wang, Jennifer Pizzano, Peter S. Dragovich, Michael Berlin and Robert L. Yauch ()
Additional contact information
Jennifer Cantley: Arvinas, LLC
Xiaofen Ye: Genentech
Emma Rousseau: Arvinas, LLC
Tom Januario: Genentech
Brian D. Hamman: HotSpot Therapeutics
Christopher M. Rose: Genentech
Tommy K. Cheung: Genentech
Trent Hinkle: Genentech
Leofal Soto: Arvinas, LLC
Connor Quinn: Arvinas, LLC
Alicia Harbin: Arvinas, LLC
Elizabeth Bortolon: Arvinas, LLC
Xin Chen: Arvinas, LLC
Roy Haskell: Arvinas, LLC
Eva Lin: Genentech
Shang-Fan Yu: Genentech
Geoff Rosario: Genentech
Emily Chan: Genentech
Debra Dunlap: Genentech
Hartmut Koeppen: Genentech
Scott Martin: Genentech
Mark Merchant: Genentech
Matt Grimmer: Genentech
Fabio Broccatelli: Genentech
Jing Wang: Arvinas, LLC
Jennifer Pizzano: Arvinas, LLC
Peter S. Dragovich: Genentech
Michael Berlin: Arvinas, LLC
Robert L. Yauch: Genentech

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract The mammalian SWItch/Sucrose Non-Fermentable (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 selective SMARCA2 inhibition is likely essential to afford an acceptable therapeutic index, and realizing this objective is challenging due to the homology with the SMARCA4 paralog. Herein we report the discovery of a potent and selective SMARCA2 proteolysis-targeting chimera molecule (PROTAC), A947. Selective SMARCA2 degradation is achieved in the absence of selective SMARCA2/4 PROTAC binding and translates 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 reveal no unexpected off-target degradation related to A947 treatment. Our study thus highlights the ability to transform a non-selective SMARCA2/4-binding ligand into a selective and efficacious in vivo SMARCA2-targeting PROTAC, and thereby provides a potential new therapeutic opportunity for patients whose tumors contain SMARCA4 mutations.

Date: 2022
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DOI: 10.1038/s41467-022-34562-5

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