Abstract 5687: Selective, chemically-induced degradation of BRM (SMARCA2) enables in vivo efficacy in BRG1 (SMARCA4)-deficient xenograft tumor models

Abstract

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 <1 nM and BRG1/BRM DC50 ratios >25. Importantly, selective BRM degradation can be achieved in the absence of selective PROTAC® binding (BRG1/BRM Kd ratios <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.

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

“…208 ACBI2 displayed selective degradation of SMARCA2 over SMARCA4 in ex vivo and in vivo assays, though it achieved tumor stasis only in vivo despite efficient SMARCA2 degradation (for SMARCA2, DC 50 = 1 nM and D max = 81%; for SMARCA4, DC 50 = 32 nM and D max = 67%). 208 Subsequent reports unveiled A947 (for SMARCA2, DC 50 = 0.039 nM and D max = 96%; for SMARCA4, DC 50 = 1.1 nM and D max = 92%) 209 and SMD-3040 (for SMARCA2, DC 50 = 12 211 While potential differences in cellular adaptation as a cause for the often observed tumor stasis rather than regression in in vivo models have been acknowledged, more potent PROTACs (D max > 95%) 212 or rational drug combinations are being explored as a means of potentiating the activity of PROTACs against tumor cells. In this regard, MCL1 protein is being evaluated as a synergistic partner for SMARCA2 degradation across various SMARCA4 mutated models, underscoring broader applicability beyond specific cellular contexts.…”