Abstract 5765: Discovery of QLS1522, a mutant-selective allosteric PI3Kα inhibitor for the treatment of PIK3CA-mutant solid tumors

Abstract Background: PIK3CA is a predominant oncogene in human cancers. While approved PI3Kα inhibitors like Alpelisib validate that PI3Kα blockade can suppress tumors and improve outcomes in PIK3CA-mutant ER+HER2- breast cancer, their major on-target toxicity against wild-type PI3Kα interferes with regulation of glucose metabolism which reduces their therapeutic index and limits clinical efficacy. Development of PIK3CA mutant selective inhibitors can significantly improve therapeutic window and anti-tumor efficacy by substantially reducing side effects. Experimental procedures: The enzymatic activity was evaluated in biochemical and biophysical assays. Viability of cell lines was measured using CellTiterGlo®. Antitumor activity was evaluated in ER+ breast cancer cell line-derived xenograft (CDX) models with either kinase domain or helical domain mutations. The impact on glucose metabolism was analyzed using an oral glucose tolerance test (OGTT). Results: QLS1522 is a potent, selective allosteric PI3Kα inhibitor designed to spare wild-type PI3Kα. It exhibited nanomolar potency against the PIK3CA H1047R mutation with high selectivity over wild-type PI3Kα and other isoforms (β, γ, δ). In a 447-kinase selectivity panel, QLS1522 showed outstanding specificity, with only Aurora-B kinase exhibiting 50% inhibition at 10 µM (IC50 of 7.8 µM for QLS1522 vs. 1.4 µM for STX-478). Cell panel studies revealed that QLS1522 exerted broad inhibitory effects across cancer cell lines carrying either kinase domain or helical domain mutations. In comparative analyses with other clinical-stage candidates such as STX-478 and RLY-2608, QLS1522 showed enhanced inhibition of pAKT in the T47D breast cancer cell line harboring the PIK3CA H1047R mutation. Notably, it maintained selectivity comparable to STX-478 and better than RLY-2608 in wild-type SKBR3 cells. In vivo, QLS1522 was well tolerated and exhibited potent antitumor efficacy in multiple ER+ breast cancer CDX models, without inducing significant glucose metabolism abnormalities. The combination of QLS1522 with standard-of-care (SoC) agents resulted in enhanced efficacy compared to monotherapy or SoC alone. QLS1522 demonstrated a favorable drug-like profile, characterized by superior solubility, permeability, and excellent pharmacokinetic properties across species, with a wide therapeutic window. Conclusions: QLS1522 is a mutant-selective allosteric PI3Ka inhibitor and represents a promising therapeutic candidate for treating PIK3CA-mutant solid tumors. IND-enabling studies are currently in progress. Citation Format: Yuxing Zhang, Hua Qin, Jiasheng Fu, Naijie Fu, Difei Dong, Changliang He, Lan Zhang, Yu Zhang, Ling Li, Jun Mao, Jianping Chen, Weibo Zhu, Dong Yang, Xinghua Cheng, Guqin Shi, Jinxiao Bao, Ying Wang, Ping Chen, Su Qian, Liang Xie, Daqing Sun, Weikang Tao. Discovery of QLS1522, a mutant-selective allosteric PI3Kα inhibitor for the treatment of PIK3CA-mutant solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5765.