Abstract 5977: Identification and characterization of an allosteric and mutant-selective PI3Kα inhibitor

Abstract Introduction: The PI3K-AKT-mTOR signaling pathway is pivotal in tumorigenesis. PIK3CA, a PI3K isoform, is one of the most frequently mutated genes, occurring in approximately 14% of cancers and in up to 40% of breast cancers. PIK3CA mutations are highly enriched at “hotspot” amino acid sites in the helical domain (E542K, E545K) and kinase domain (H1047R/L). PI3Kα mutations are often oncogenic drivers of other refractory cancers, including gastric cancer, colon cancer, uterine cancer, and head and neck squamous cell carcinoma. Orthosteric inhibitors of PI3Kα, such as alpelisib and inavolisib have been approved for the treatment of patients with advanced HR+/HER2− breast cancer. However, alpelisib and inavolisib lack mutant selectivity and inhibit WT PI3Kα, which plays a critical role in cellular glucose homeostasis, resulting in dose-limiting toxicity such as hyperglycemia and hyperinsulinemia. Selective targeting of mutant PI3Kα is anticipated to enhance antitumor efficacy and mitigate the toxicity associated with wild-type PI3Kα inhibition in normal tissues. Multiple allosteric and mutant-selective PI3Kα inhibitors have been successfully developed into clinical stage, including LOXO-783 (NCT05307705), RLY-2608 (NCT05216432) and STX-478 (NCT05768139). TY-2291 is an allosteric and mutant-selective PI3Kα inhibitor developed by TYK Medicines Inc. Results: TY-2291 is a potent kinase inhibitor of mutant PI3Kα with high selectivity over WT PI3Kα. In in vitro antiproliferative test, TY-2291 showed better antiproliferative activity against multiple PI3Kα mutant cells than LOXO-783, STX-478, and RLY-2608. In the mouse HCC1954 CDX model, TY-2291 showed potent tumor-inhibitory activity and excellent tolerance. TY-2291 also demonstrated excellent DMPK properties and desirable drug-like properties. In the insulin tolerance test, TY-2291 had no effect on fasting plasma glucose levels after four days of treatment. In conclusion, we have identified a potent allosteric and mutant-selective PI3Kα inhibitor. Our findings indicate that TY-2291 may significantly enhance the therapeutic index of PI3Kα-mutant cancers in the absence of PI3Kα WT-related toxicities. Citation Format: Chengshan Niu, Shengli Dong, Shaoqing Chen, Kaige Ji, Maolin Zheng, Mingtao Chen, Yuanjie Li, Meihua Li, Zhengfei Guo, Hongqiang Li, Yu Yu, Xinlong Yang, Chao Zhou, Apeng Liang, Yin Zhou, Wei Wu, Mingyu Jiang, Jun Li, Yusheng Wu. Identification and characterization of an allosteric and mutant-selective PI3Kα 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 5977.