Abstract PR03: Selective degradation of mutant PIK3CA promotes increased mutant specificity in a subset of PI3K ATP-competitive inhibitors

摘要: Activating mutations in PIK3CA are among the most significant oncogenic events across all cancers, making it an important target for drug development. Yet application of PI3K inhibitors clinic has been limited by difficulty achieving adequate therapeutic window, due to critical role that signaling plays normal physiologic processes, such as glucose homeostasis. In theory, window could be improved if were possible design mutant selective inhibitors, demonstrated with other oncogenes EGFR. However, unlike EGFR, predominant activating do not reside kinase active site, presenting a major challenge rational structure-based design. Nevertheless, was recently shown inhibitor taselisib is able achieve modest levels selectivity both cancer lines well cell engineered express or wild-type PIK3CA. Taselisib also selectively induce degradation versus PIK3CA, leading speculation this may responsible observed selectivity. order better understand origins and several we assessed these variety biophysical biochemical assays under conditions designed mimic settings. parallel, investigated mechanistic basis our lines. Our results consistent hypothesis mechanism underlying class site inhibitors. This abstract being presented Poster B03. Citation Format: Lan Nguyen, Kyle Edgar, Kyung Song, Stephen Schmidt, Victorai Schutz, Noriko Ishisoko, Eric Torres, Akash Das, Divya Murali, Steve Sideris, Timothy Wendorff, Matt Saabye, Hans Purkey, Jawahar Sudhamsu, Steven Staben, Emily Hanan, Georgia Hatzivassiliou, Lori Friedman, Nicholas F. Endres. Selective promotes increased specificity subset ATP-competitive [abstract]. In: Proceedings AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr PR03.