Abstract 3004: Preclinical characterization of CGT6297, a novel PI3Kα H1047R mutant-selective inhibitor

Abstract PIK3CA encodes the p110α catalytic subunit of PI3-kinase alpha (PI3Kα) and is the most frequently mutated kinase in human cancer with common mutations occurring in the kinase domain (H1047R) and helical domain (E542K/E545K). The approved PI3Kα inhibitor, alpelisib, shows promise for this targeted class of agents with improvements in progression-free survival in ER+/Her2- breast cancer patients in combination with fulvestrant. However, toxicities attributed to the inhibition of wild-type PI3Kα, such as hyperglycemia, gastrointestinal issues, and skin reactions, lead to sub-optimal target engagement due to requisite dosing modifications. A PI3K mutant inhibitor that spares WT PI3K is predicted to be better tolerated, require fewer dosing modifications, and therefore, have the potential to provide improved clinical benefit. Herein, we present the preclinical characterization of CGT6297, a wild type sparing PI3Kα H1047R inhibitor. Citation Format: Aaron C. Smith, Ben Arwood-Levine, Abiezer Blandon, Alexandra Born, Richard Brizendine, Payal Chatterjee, Mark J. Chicarelli, Michael L. Conner, Brad Fell, Jennifer Fulton, Anna Guarnieri, Hannah Hubert, Ravi Jalluri, Hailey Knox, Keith Koch, Daniel Krischlunas, Vijay Kumar, Sara Kuzbiel, Matt McDonald, Colin McHugh, Brent Mclean, Kelsey W. Nassar, Paul Larsen, Brad Newhouse, Scott Niman, Rob Rieger, John Robinson, Marelí Rodriguez, Leah Salituro, Vinny Scarato, Lee Stunkard, Francis Sullivan, Patrick Sutter, Roy Turton, Rob Van Gulick, Brooklynn Venteicher, Logan Vine, Shannon Winski, Shannon Winski, Hannah Work, Yeyun Zhou. Preclinical characterization of CGT6297, a novel PI3Kα H1047R mutant-selective inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3004.