Discovery and characterization of RGT-490, a mutant selective PI3Kalpha inhibitor

PI3Kalpha 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 PI3Kalpha inhibitors alpelisib and inavolisib are limited by the side effects associated with wild-type (WT) PI3Kalpha inhibition, prominently hyperglycemia, rash, stomatitis and GI toxicities. RGT-490 is a potent and mutant selective PI3Kalpha 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 PI3Kalpha 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 PI3Kalpha mutation. With potent activity and excellent selectivity, RGT-490 provides opportunity to reduce WT PI3Kalpha-associated toxicities, enable deeper target coverage and achieve further improved clinical efficacy in PI3Kalpha mutant patients. RGT-490 phase 1 study is planned 1H2026.