1区 · 医学
Article
作者: Ye, Xiaofen ; Quinn, Connor ; Berlin, Michael ; Chen, Huifen ; Harbin, Alicia ; Li, Limei ; Cantley, Jennifer ; Pizzano, Jennifer ; Wang, Jing ; Hamman, Brian D ; Chan, Emily W ; Davenport, Kim ; Soto, Leofal ; DiNicola, Dean ; Gordon, Debbie ; Staben, Leanna R ; Pérez-Dorado, Inmaculada ; Cheng, Yunxing ; He, Mingtao ; Januario, Thomas ; Rose, Christopher M ; Tian, Qingping ; Hole, Alison J ; Bookbinder, Mark ; Ye, Crystal S ; Sun, Hongming ; Wang, Weifeng ; Zhang, Penghong ; Dragovich, Peter S ; Bortolon, Elizabeth ; Yauch, Robert ; Chen, Xin ; Cheung, Tommy K ; Broccatelli, Fabio ; Merchant, Mark ; Koenig, Stefan G ; Rousseau, Emma ; Haskell, Roy ; Cadelina, Greg ; Kerry, Philip S ; Zhou, Yuhui
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.