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