Q1 · MEDICINE
Article
Author: Pérez-Dorado, Inmaculada ; Yauch, Robert ; Bookbinder, Mark ; Harbin, Alicia ; Dragovich, Peter S. ; He, Mingtao ; Haskell, Roy ; Berlin, Michael ; Koenig, Stefan G. ; Chen, Huifen ; Pizzano, Jennifer ; Quinn, Connor ; Ye, Xiaofen ; Davenport, Kim ; Hole, Alison J. ; Wang, Jing ; Zhou, Yuhui ; Li, Limei ; Ye, Crystal S. ; Januario, Thomas ; Wang, Weifeng ; Cadelina, Greg ; Broccatelli, Fabio ; Staben, Leanna R. ; Cantley, Jennifer ; Kerry, Philip S. ; Merchant, Mark ; Zhang, Penghong ; Bortolon, Elizabeth ; Sun, Hongming ; Chen, Xin ; Hamman, Brian D. ; Tian, Qingping ; Chan, Emily W. ; Soto, Leofal ; Cheng, Yunxing ; Rose, Christopher M. ; Gordon, Debbie ; Cheung, Tommy K. ; DiNicola, Dean ; Rousseau, Emma
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.