AbstractPIK3CA, which encodes p110α, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kα), is one of the most frequently mutated oncogenes and dysregulated PI3Kα activity is important for tumor growth. Up to 40% of hormone receptor (HR)-positive breast cancer (BrCA) tumors and 13% of all solid tumors harbor PIK3CA mutations, with the majority of mutations occurring within p110α kinase and helical domains. Orthosteric ATP-competitive inhibitors, alpelisib and inavolisib, which inhibit both Wild-type (WT) and mutant PI3Kα, are approved in combination regimens for treating PIK3CA-mutant, HR+/HER2-, advanced or metastatic BrCA. However, because PI3Kα is critical for insulin signaling, inhibition of WT PI3Kα results in hyperglycemia, and limits the clinical utility of these inhibitors. To overcome this limitation, ETX-636 was designed as an allosteric, pan-mutant-selective PI3Kα inhibitor and degrader by leveraging our Kinetic Ensemble® platform for optimal binding to a unique metastable state of p110α. In addition to greater biochemical selectivity for mutant PI3Kα over WT PI3Kα, ETX-636 has stronger target binding affinity, better on-target potency in biochemical and cellular pharmacodynamic assays, and demonstrates superior anti-tumor activity in vivo when compared to other allosteric, pan-mutant-selective PI3Kα inhibitors (i.e. RLY-2608 and STX-478). In viability assays run on a panel of 65 cancer cell lines, the presence of PIK3CA mutations was a strong predictor of ETX-636 sensitivity and ETX-636 potency was superior to both RLY-2608 and STX-478. In vitro and in vivo mechanistic studies revealed ETX-636 induces significant proteasome-dependent degradation of mutant p110α, while sparing WT protein (a feature not seen with other pan-mutant allosteric inhibitors), resulting in more durable pathway inhibition. ETX-636 dosed orally, once daily, results in deep and durable pathway inhibition and induces tumor regression in kinase and helical domain PIK3CA-mutant xenografts. In an ER-positive, HER2-negative, PI3Kα-mutant BrCA xenograft, ETX-636 is efficacious as a single agent and shows synergistic activity with fulvestrant, inducing tumor regression while being well-tolerated. Blood glucose levels after dosing in multiple species indicate that ETX-636 does not disrupt glucose homeostasis at efficacious exposures, even under non-fasting conditions. In addition, based on pharmacokinetic, pharmacodynamic, efficacy, and toxicology studies, predicted human efficacious doses of ETX-636 are not projected to cause hyperglycemia. The preclinical profile of ETX-636 underscores its best-in-class potential as an allosteric pan-mutant-selective PI3Kα dual inhibitor and degrader, and supports its clinical development both in single agent and combination clinical trials in patients with PIK3CA-mutant tumors, including HR+/PIK3CA-mutant BrCA.Citation Format:Robert F. Koncar, Mingzong Li, Jingyan Gao, Fei Pang, Ying Lin, Raj Nagaraja, Yong Tang, Hannah Szeto, Zipeng Fan, Karan Kapoor, Robbie Chen, Eric Simone, Minghong Hao, Shengfang Jin, Tao Liu, Meghana Kulkarni, Jeffery Kutok. ETX-636, a novel allosteric pan-mutant-selective PI3Kα dual inhibitor and degrader with best-in-class potential [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 1659.