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BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Ka interaction

  1. Author:
    Simanshu,Dhirendra [ORCID]
    Xu, Rui [ORCID]
    Stice, James P [ORCID]
    Czyzyk,Daniel [ORCID]
    Feng, Siyu [ORCID]
    Denson,John-Paul [ORCID]
    Riegler, Erin [ORCID]
    Yang, Yue [ORCID]
    Zhang, Cathy
    Donovan, Sofia [ORCID]
    Smith,Brian
    Abreu-Blanco, Maria [ORCID]
    Chen, Ming
    Feng, Cindy [ORCID]
    Fu, Lijuan [ORCID]
    Rabara,Dana [ORCID]
    Young, Lucy C [ORCID]
    Dyba,Marcin [ORCID]
    Yan, Wupeng [ORCID]
    Lin, Ken [ORCID]
    Ghorbanpoorvalukolaie, Samar [ORCID]
    Larsen,Erik [ORCID]
    Malik, Wafa [ORCID]
    Champagne, Allison [ORCID]
    Parker, Katie
    Ju, Jin Hyun [ORCID]
    Jeknic, Stevan [ORCID]
    Esposito,Dominic [ORCID]
    Turner, David M [ORCID]
    Lightstone, Felice C [ORCID]
    Wang, Bin [ORCID]
    Wehn, Paul M [ORCID]
    Wang, Keshi
    Stephen,Andrew [ORCID]
    Maciag,Anna
    Hata, Aaron N [ORCID]
    Sinkevicius, Kerstin W [ORCID]
    Nissley, Dwight V [ORCID]
    Wallace, Eli M [ORCID]
    McCormick, Frank [ORCID]
    Beltran, Pedro J [ORCID]

  2. Author Address

    NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA., BridgeBio Oncology Therapeutics, South San Francisco, CA, USA., Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA, USA., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Massachusetts General Hospital Cancer Center, Boston, MA, USA, and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., BridgeBio Pharma, San Francisco, CA, USA.,
    1. Year: 2025
    2. Date: Jun 12
    3. Epub Date: 2025 06 12
  2. Journal: Science (New York, N.Y.)
    1. Pages: eadq2004
  4. Type of Article: Article
  5. Article Number: eadq2004
  1. Abstract:

    BBO-10203 is an orally available drug that covalently and specifically binds to the RAS-binding domain of phosphoinositide 3-kinase a (PI3Ka), preventing its activation by HRAS, NRAS, and KRAS. It inhibited PI3Ka activation in tumors with oncogenic mutations in KRAS or PIK3CA, and in tumors with human epidermal growth factor receptor 2 (HER2) amplification or overexpression. In preclinical models, BBO-10203 caused significant tumor growth inhibition across multiple tumor types and showed enhanced efficacy in combination with inhibitors of cyclin-dependent kinase 4/6 (CDK4/6), estrogen receptor (ER), HER2 and KRAS-G12C mutant, including in tumors harboring mutations in Kelch-like ECH-associated protein 1 (KEAP1) and Serine/Threonine Kinase 11 (STK11). Notably, these antitumor effects occurred without inducing hyperglycemia, as insulin signaling does not depend on RAS-mediated PI3Ka activation to promote glucose uptake.

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External Sources

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  2. DOI: 10.1126/science.adq2004
  3. PMID: 40504949

Library Notes

  1. Fiscal Year: FY2024-2025
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