Abstract 4571: Discovery and characterization of RGT-490, a mutant selective PI3Kα inhibitor

Abstract PI3Kα is frequently mutated and overactivated in a variety of human cancers including breast, gynecological, head and neck, and colorectal cancers. Clinical use and efficacy of the approved PI3Kα inhibitors alpelisib and inavolisib are limited by the side effects associated with wild-type (WT) PI3Kα inhibition, prominently hyperglycemia, rash, stomatitis and GI toxicities. RGT-490 is a potent and mutant selective PI3Kα inhibitor discovered by deploying Computer Accelerated Rational Design (CARD) technology platform. It demonstrated potent anti-proliferation activity in PIK3CA mutated cancer cells. In ER+ breast cancer T47D xenograft model, RGT-490 robustly suppressed Akt phosphorylation and induced significant apoptosis without increasing insulin or glucose levels. In addition, RGT-490 caused near-complete tumor regressions in T47D models without any apparent toxicity. As an allosteric PI3Kα inhibitor, RGT-490 overcame the resistance to orthosteric inhibitors alpelisib and inavolisib resulted from the secondary mutations in the ATP binding pocket. In HER2+ breast cancer HCC1954 cells, RGT-490 suppressed the resistance to HER2 inhibition caused by PI3Kα mutation. With potent activity and excellent selectivity, RGT-490 provides opportunity to reduce WT PI3Kα-associated toxicities, enable deeper target coverage and achieve further improved clinical efficacy in PI3Kα mutant patients. RGT-490 phase 1 study is planned 1H2026. Citation Format: Jing Han, Kailiang Wang, Feng Zhao, Xinjuan Wang, Xiaoming Ren, Xiuliang Huang, Xiumei Chen, Teng Feng, Xin Hua, Zhuanzhuan Zhang, Lili Yao, Jing Lin, Wenge Zhong, Julie Xie. Discovery and characterization of RGT-490, a mutant selective PI3Kα inhibitor [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 4571.