Abstract 5687: Selective, chemically-induced degradation of BRM (SMARCA2) enables in vivo efficacy in BRG1 (SMARCA4)-deficient xenograft tumor models
Authors: Berlin Michael , Cantley Jennifer , Wang Jing , Bookbinder Mark , Cadelina Gregory , Chan Emily , Chen Huifen , Chen Xin , Davenport Kim , Fernando Tharu , Gordon Debbie , Hamman Brian , Haskell Roy , Ishchenko Alexey , Kirkpatrick Donald S. , Maher Jonathan , Merchant Mark , Moffat John , Morgan Alicia , Nguyen An , Pizzano Jennifer , Quinn Connor , Rose Christopher M. , Rousseau Emma , Sethuraman Vijay , Staben Leanna , Wilson Catherine , Ye Xiaofen , Broccatelli Fabio , Yauch Robert , Dragovich Peter S. 
Published: September 2020

The mammalian SWI/SNF complex catalyzes the remodeling of chromatin through the helicase activity of two mutually-exclusive, paralogous subunits, BRG1 and BRM. BRG1 is frequently mutated in cancer and its inactivation results in a cellular dependence on BRM. Despite the attractiveness of BRM as a synthetic lethal therapeutic target, the selective inhibition of BRM represents a considerable challenge due to the high degree of homology between BRM and BRG1. Furthermore, published data indicate that achieving such selectivity is likely essential to afford an acceptable therapeutic index. We sought to mimic the synthetic lethality observed in BRG1-mutant cancers by identifying proteolysis-targeting chimera (PROTAC®) molecules capable of selectively degrading BRM via trimeric complex formation with the von Hippel-Lindau (VHL) E3 ligase. In this disclosure, we report our initial discovery of potent and selective chimeric BRM-degrader molecules which exhibit BRM DC50 values &lt;1 nM and BRG1/BRM DC50 ratios &gt;25. Importantly, selective BRM degradation can be achieved in the absence of selective PROTAC® binding (BRG1/BRM Kd ratios &lt;2). Global ubiquitin mapping and proteome profiling reveal no unexpected off-target activity of the selective BRM PROTAC® degraders. Treatment of a panel of NSCLC cell lines with a representative degrader molecule resulted in enhanced growth inhibition in BRG1-mutant relative to BRG1-wild-type cell lines. We also demonstrate that intermittent intravenous administration of an optimized BRM PROTAC® degrader exhibited strong in vivo modulation of pharmacodynamic biomarkers and afforded tumor growth inhibition in several BRG1-mutant xenograft models. Our study thus highlights the ability to transform a non-selective BRM-binding ligand into a selective and efficacious in vivo BRM PROTAC® degrader.

Citation Format: Michael Berlin, Jennifer Cantley, Jing Wang, Mark Bookbinder, Gregory Cadelina, Emily Chan, Huifen Chen, Xin Chen, Kim Davenport, Tharu Fernando, Debbie Gordon, Brian Hamman, Roy Haskell, Alexey Ishchenko, Donald S. Kirkpatrick, Jonathan Maher, Mark Merchant, John Moffat, Alicia Morgan, An Nguyen, Jennifer Pizzano, Connor Quinn, Christopher M. Rose, Emma Rousseau, Vijay Sethuraman, Leanna Staben, Catherine Wilson, Xiaofen Ye, Fabio Broccatelli, Robert Yauch, Peter S. Dragovich. Selective, chemically-induced degradation of BRM (SMARCA2) enables in vivo efficacy in BRG1 (SMARCA4)-deficient xenograft tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5687.