Abstract P4-12-19: Preclinical Characterization of a Novel PI3Kα H1047R Mutant-Selective Inhibitor

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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 in vitro and in vivo activity of a novel, wild type sparing PI3Kα inhibitor series which is potent against the oncogenic H1047R mutation. 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 J. Knox, Keith Koch, Daniel Krischlunas, Vijay Kumar, Sara Kuzbiel, Colin McHugh, Brent Mclean, Kelsey W. Nassar, Brad Newhouse, Scott Niman, Rob Rieger, John Robinson, Marelí Rodriguez, Leah Salituro, Vincent Scarato, Lee Stunkard, Francis Sullivan, Patrick Sutter, Roy Turton, Robb Van Gulick, Brooklynn Venteicher, Logan E. Vine, Shannon Winski, Yeyun Zhou. Preclinical Characterization of a Novel PI3Kα H1047R Mutant-Selective Inhibitor [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-12-19.

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