LY4045004

LY4045004 is a next-generation, orally administered, mutant-selective phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor developed by Eli Lilly. It is designed to selectively inhibit PI3Kα mutants—specifically kinase-domain (H1047R) and helical-domain (E545K) mutations—while sparing wild-type PI3Kα and not inhibiting other PI3K isoforms. This selectivity aims to reduce toxicity associated with wild-type inhibition, such as hyperglycemia. Preclinical studies have shown that LY4045004 induces dose-dependent tumor regression in breast cancer models harboring these mutations both as monotherapy and in combination with fulvestrant, without significant metabolic side effects or weight changes. The drug is being developed primarily for hormone receptor-positive (HR+), HER2-negative breast cancer with prevalent PIK3CA mutations[1][2][3][5][6].