2. Academic Validation
  3. Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers

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

  • Nat Commun. 2022 Nov 10;13(1):6814. doi: 10.1038/s41467-022-34562-5.
Jennifer Cantley 1,  Xiaofen Ye 2,  Emma Rousseau 1,  Tom Januario 2,  Brian D Hamman 3,  Christopher M Rose 2,  Tommy K Cheung 2,  Trent Hinkle 2,  Leofal Soto 1,  Connor Quinn 1,  Alicia Harbin 1,  Elizabeth Bortolon 1,  Xin Chen 1,  Roy Haskell 1,  Eva Lin 2,  Shang-Fan Yu 2,  Geoff Del Rosario 2,  Emily Chan 2,  Debra Dunlap 2,  Hartmut Koeppen 2,  Scott Martin 2,  Mark Merchant 2,  Matt Grimmer 2,  Fabio Broccatelli 2,  Jing Wang 1,  Jennifer Pizzano 1,  Peter S Dragovich 2,  Michael Berlin 1,  Robert L Yauch 4
Affiliations

Affiliations

  • 1 Arvinas, LLC, 5 Science Park, New Haven, CT, 06511, USA.
  • 2 Genentech, 1 DNA Way, South San Francisco, 94080, USA.
  • 3 HotSpot Therapeutics, Inc. 1 Deerpark Dr., Ste C, Monmouth Junction, NJ, 08852, USA.
  • 4 Genentech, 1 DNA Way, South San Francisco, 94080, USA. bobyauch@gene.com.
PMID: 36357397 DOI: 10.1038/s41467-022-34562-5
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.

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