OKI-219

OKI-219 is an orally bioavailable, small molecule inhibitor that selectively targets the PI3Kα H1047R mutant, a common oncogenic driver mutation in various solid tumors, particularly breast cancer. It demonstrates approximately 100-fold selectivity for the H1047R mutant over wild-type PI3Kα and shows minimal off-target kinase inhibition across a broad panel. Preclinical studies indicate that OKI-219 reduces phosphorylated AKT (pAKT) and proliferation specifically in PI3Kα H1047R-mutant cell lines, with dose-dependent antitumor activity observed in xenograft models. In clinical trials, it has shown favorable pharmacokinetics and safety profiles with no significant hyperglycemia or severe adverse events reported to date. The drug is being developed by OnKure Therapeutics as both monotherapy and in combination with endocrine therapies (such as fulvestrant) or HER2-targeted therapy for advanced solid tumors and breast cancer[1][2][4][5][6].