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bioRxiv · 10.64898/2026.01.16.699992

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

Wang, Q.·Cheng, H.·Yu, X.·Qian, C.·Ji, R.-L.·Roberts, T. M.·Kerns, W. D.·Zhao, J. J.
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Abstract

PI3K{beta} is a critical oncogenic driver in cancers harboring PTEN loss or PIK3CB alterations, yet effective and selective PI3K{beta}-targeted therapies remain elusive. Here, we report the development and preclinical characterization of GT220, a highly selective and potent small-molecule PI3K{beta} inhibitor developed through integrated artificial-intelligence-driven design with medicinal chemistry and pharmacologic optimization. GT220 exhibits exceptional biochemical selectivity for PI3K{beta}, 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 PI3K-dependent cells. In vivo, GT220 achieves a favorable tumor exposure with sustained PI3K{beta} 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 PI3K-dependent tumors, underscoring its context-dependent mechanism of action. Collectively, these findings establish GT220 as a promising next-generation PI3K{beta} inhibitor and provide a strong preclinical rationale for precision targeting of PI3K{beta}-dependent cancers.

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Wang, Q., Cheng, H., Yu, X., Qian, C., Ji, R.-L., Roberts, T. M., Kerns, W. D., Zhao, J. J.. 2026-01-18. Targeting PI3Kβ-dependent cancer with a novel small molecule inhibitor, GT220. https://doi.org/10.64898/2026.01.16.699992

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