Targeting PI3Kβ-dependent cancer with a novel small molecule inhibitor, GT220

Abstract PI3Kβ is a critical oncogenic driver in cancers harboring PTEN loss or PIK3CB alterations, yet effective and selective PI3Kβ-targeted therapies remain elusive. Here, we report the development and preclinical characterization of GT220, a highly selective and potent small-molecule PI3Kβ inhibitor developed through integrated artificial-intelligence–driven design with medicinal chemistry and pharmacologic optimization. GT220 exhibits exceptional biochemical selectivity for PI3Kβ, binding with sub-nanomolar affinity and with minimal activity against other class I PI3K isoforms or the broader protein kinome. In cellular models, GT220 potently suppresses AKT phosphorylation and selectively inhibits viability of PTEN-deficient cancer cells, while sparing PTEN/PIK3CB wild-type and PI3Kα-dependent cells. In vivo, GT220 achieves a favorable tumor exposure with sustained PI3Kβ pathway inhibition and demonstrates robust antitumor efficacy and good tolerability in PTEN-deficient breast cancer xenograft models. In contrast, GT220 shows no antitumor activity or pathway inhibition in PTEN-wild-type or PI3Kα-dependent tumors, underscoring its context-dependent mechanism of action. Collectively, these findings establish GT220 as a promising next-generation PI3Kβ inhibitor and provide a strong preclinical rationale for precision targeting of PI3Kβ-dependent cancers.