BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction.
作者信息
Simanshu Dhirendra K, Xu Rui, Stice James P, Czyzyk Daniel J, Feng Siyu, Denson John-Paul, Riegler Erin, Yang Yue, Zhang Cathy, Donovan Sofia, Smith Brian P, Abreu-Blanco Maria, Chen Ming, Feng Cindy, Fu Lijuan, Rabara Dana, Young Lucy C, Dyba Marcin, Yan Wupeng, Lin Ken, Ghorbanpoorvalukolaie Samar, Larsen Erik K, Malik Wafa, Champagne Allison, Parker Katie, Ju Jin Hyun, Jeknic Stevan, Esposito Dominic, Turner David M, Lightstone Felice C, Wang Bin, Wehn Paul M, Wang Keshi, Stephen Andrew G, Maciag Anna E, Hata Aaron N, Sinkevicius Kerstin W, Nissley Dwight V, Wallace Eli M, McCormick Frank, Beltran Pedro J
机构信息
National Cancer Institute (NCI) RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD, USA.
BridgeBio Oncology Therapeutics, South San Francisco, CA, USA.
出版信息
Science. 2025 Jul 24;389(6758):409-415. doi: 10.1126/science.adq2004. Epub 2025 Jun 12.
BBO-10203 is an orally available drug that covalently and specifically binds to the rat sarcoma (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 or 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, because insulin signaling does not depend on RAS-mediated PI3Kα activation to promote glucose uptake.
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