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Ref Type Journal Article
PMID (40504949)
Authors Simanshu DK, Xu R, Stice JP, Czyzyk DJ, Feng S, Denson JP, Riegler E, Yang Y, Zhang C, Donovan S, Smith BP, Abreu-Blanco M, Chen M, Feng C, Fu L, Rabara D, Young LC, Dyba M, Yan W, Lin K, Ghorbanpoorvalukolaie S, Larsen EK, Malik W, Champagne A, Parker K, Ju JH, Jeknic S, Esposito D, Turner DM, Lightstone FC, Wang B, Wehn PM, Wang K, Stephen AG, Maciag AE, Hata AN, Sinkevicius KW, Nissley DV, Wallace EM, McCormick F, Beltran PJ
Title BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction.
Journal Vol Issue Date Pages Journal Short Title
Science (New York, N.Y.) 2025 Jun 12 eadq2004 Science
URL
Abstract Text BBO-10203 is an orally available drug that covalently and specifically binds to the RAS-binding domain of phosphoinositide 3-kinase α (PI3Kα), preventing its activation by HRAS, NRAS, and KRAS. It inhibited PI3Kα 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 PI3Kα activation to promote glucose uptake.

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