PROTACs Targeting BRM (SMARCA2) Afford Selective <i>In Vivo</i> Degradation over BRG1 (SMARCA4) and Are Active in BRG1 Mutant Xenograft Tumor Models
Michael Berlin, Jennifer Cantley, Mark Bookbinder, Elizabeth Bortolon, Fabio Broccatelli, Greg Cadelina, Emily Chan, Huifen Chen, Xin Chen, Yunxing Cheng, Tommy K. Cheung, Kim Davenport, Dean DiNicola, Debbie Gordon, Brian D. Hamman, Alicia Harbin, Roy Haskell, Mingtao He, Alison J. Hole, Thomas Januario, Philip S. Kerry, Stefan G. Koenig, Limei Li, Mark Merchant, Inmaculada Pérez‐Dorado, Jennifer Pizzano, Connor Quinn, Christopher M. Rose, Emma Rousseau, Leofal Soto, Leanna R. Staben, Hongming Sun, Qingping Tian, Jing Wang, Weifeng Wang, C Ye, Xiaofen Ye, Penghong Zhang, Yuhui Zhou, Robert L. Yauch, Peter S. Dragovich
Abstract
The identification of VHL-binding proteolysis targeting chimeras (PROTACs) that potently degrade the BRM protein (also known as SMARCA2) in SW1573 cell-based experiments is described. These molecules exhibit between 10- and 100-fold degradation selectivity for BRM over the closely related paralog protein BRG1 (SMARCA4). They also selectively impair the proliferation of the H1944 “BRG1-mutant” NSCLC cell line, which lacks functional BRG1 protein and is thus highly dependent on BRM for growth, relative to the wild-type Calu6 line. In vivo experiments performed with a subset of compounds identified PROTACs that potently and selectively degraded BRM in the Calu6 and/or the HCC2302 BRG1 mutant NSCLC xenograft models and also afforded antitumor efficacy in the latter system. Subsequent PK/PD analysis established a need to achieve strong BRM degradation (>95%) in order to trigger meaningful antitumor activity in vivo . Intratumor quantitation of mRNA associated with two genes whose transcription was controlled by BRM ( PLAU and KRT80 ) also supported this conclusion.