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Rate Of ReturnBBOT develops selective PI3Kα inhibitor BBO-10203 with both anti-tumor and metabolic safety
BridgeBio Oncology Therapeutics (BBOT) is a subsidiary of $Bridgebio Pharma(BBIO.US), spun off from its parent company in May 2024. BBOT plans to achieve independent listing through a SPAC merger with $Helix Acquisition Corp II(HLXB.US), and will trade on NASDAQ (ticker: BBOT), expected to be completed in the third quarter of 2025.
The PI3Kα pathway plays a central role in tumor signal transduction, with PIK3CA mutations and excessive activation of RAS proteins driving the progression of various cancers. Traditional PI3Kα inhibitors (such as alpelisib) target the kinase domain but often cause hyperglycemia due to interference with insulin signaling.
On July 24, BridgeBio Oncology Therapeutics' Pedro J. Beltran, the National Cancer Institute's Frank McCormick, and Dhirendra K. Simanshu published a paper in Science titled "BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction." The developed BBO-10203 provides a new strategy by selectively blocking the interaction between RAS proteins (HRAS, NRAS, KRAS) and the RAS-binding domain (RBD) of PI3Kα. This covalent inhibitor binds to the C242 residue of the PI3Kα RBD, sterically blocking RAS binding while not affecting the kinase activity of PI3Kα. Structural analysis confirmed that due to the unique residues and conformational features of the PI3Kα RBD, BBO-10203 exhibits high specificity for PI3Kα.
Broad-spectrum antitumor activity across genomic subtypes
BBO-10203 demonstrated effective inhibition of PI3Kα signaling in various cancer models. In HER2-amplified tumors, the drug almost completely suppressed phosphorylated AKT (pAKT), suggesting that HER2-driven tumors are highly dependent on RAS-PI3Kα crosstalk, possibly involving non-classical RAS family proteins. Cell lines carrying PIK3CA mutations (especially helical domain variants like E545K) also showed significant sensitivity, while kinase domain mutations (such as H1047R) exhibited weaker responses due to lower RAS dependency. KRAS-mutant tumors (including G12D and G12C) showed moderate pAKT inhibition, further supporting the role of the RAS-PI3Kα axis. Notably, PTEN-deficient tumors remained resistant due to RAS-independent PI3K activation.
Synergistic combinations and overcoming resistance
The efficacy of BBO-10203 was enhanced in combination therapies. In HER2+ breast cancer models, combination with trastuzumab synergistically inhibited growth and persistently reduced pAKT, overcoming resistance mechanisms to HER2-targeted therapy. Similarly, in estrogen receptor-positive (ER+) breast cancer, combination with fulvestrant or palbociclib enhanced efficacy, highlighting the role of PI3Kα in hormone-driven proliferation. KRAS-G12C mutant lung cancers often develop adaptive resistance through PI3K pathway activation, and BBO-10203 combined with KRAS-G12C inhibitors (including tumors with KEAP1 or STK11 co-mutations) showed significant effects. Mechanistically, these combinations simultaneously inhibit MAPK and PI3K signaling, blocking key survival pathways.
Metabolic safety: A core advantage
Unlike traditional PI3Kα inhibitors, BBO-10203 does not affect glucose homeostasis. Mouse oral glucose tolerance tests showed that even at three times the therapeutic dose, it did not induce hyperglycemia or compensatory insulin secretion (as measured by C-peptide). This metabolic neutrality stems from the preservation of insulin-mediated PI3Kα activation (independent of RAS proteins). By avoiding interference with insulin signaling, BBO-10203 overcomes the dose-limiting toxicity of existing PI3Kα inhibitors, making it suitable for long-term administration.
Clinical significance and future directions
BBO-10203 represents a new paradigm in targeting PI3Kα—focusing on pathway regulation rather than catalytic inhibition. Its efficacy in RAS- and HER2-driven tumors and metabolic safety suggest broad applications in precision oncology. Ongoing clinical trials will validate whether these preclinical advantages apply to human patients, particularly in combination with CDK4/6 inhibitors, endocrine therapies, and KRAS-G12C inhibitors. If successful, BBO-10203 could fill the treatment gap for RAS-PI3Kα signal-dependent cancers while avoiding the trade-off between efficacy and metabolic toxicity.
Paper link: https://doi.org/10.1126/science.adq2004
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