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<p>In recent years, the Phosphoinositide-3-Kinase α (PI3Kα) signaling pathway has been increasingly recognized as a critical driver of tumorigenesis, particularly in breast cancer drug resistance and other solid tumors. Although conventional PI3Kα inhibitors (e.g., Alpelisib) have shown efficacy in extending progression-free survival in patients with PI3Kα-mutant breast cancer, their clinical application remains constrained by off-target toxicities, particularly hyperglycemia, which limits dosing and therapeutic feasibility. Building on recent preclinical findings, this study introduces BBO-10203, a first-in-class, orally bioavailable small-molecule inhibitor targeting the RAS-PI3Kα interaction. The compound is rationally designed to selectively and covalently bind to Cysteine 242 (Cys242) within the Rat Sarcoma (RAS)-Binding Domain (RBD) of PI3Kα, thereby effectively disrupting RAS-mediated PI3Kα activation. This unique mechanism confers potent in vivo antitumor activity while preserving insulin-regulated glucose metabolism, thereby mitigating metabolic adverse effects.</p>

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Precise regulation of RAS-Mediated PI3Kα activation: therapeutic potential of BBO-10203 in cancer treatment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Ziyi Fan,
  • Erqing Tan,
  • Bin Song

摘要

In recent years, the Phosphoinositide-3-Kinase α (PI3Kα) signaling pathway has been increasingly recognized as a critical driver of tumorigenesis, particularly in breast cancer drug resistance and other solid tumors. Although conventional PI3Kα inhibitors (e.g., Alpelisib) have shown efficacy in extending progression-free survival in patients with PI3Kα-mutant breast cancer, their clinical application remains constrained by off-target toxicities, particularly hyperglycemia, which limits dosing and therapeutic feasibility. Building on recent preclinical findings, this study introduces BBO-10203, a first-in-class, orally bioavailable small-molecule inhibitor targeting the RAS-PI3Kα interaction. The compound is rationally designed to selectively and covalently bind to Cysteine 242 (Cys242) within the Rat Sarcoma (RAS)-Binding Domain (RBD) of PI3Kα, thereby effectively disrupting RAS-mediated PI3Kα activation. This unique mechanism confers potent in vivo antitumor activity while preserving insulin-regulated glucose metabolism, thereby mitigating metabolic adverse effects.