BBO-10203是一种口服药物，共价特异性结合磷酸肌肽3-激酶α (PI3Kα)的ras结合结构域，阻止其被HRAS、NRAS和KRAS激活。在KRAS或PIK3CA基因突变的肿瘤中，以及人表皮生长因子受体2 （HER2）扩增或过表达的肿瘤中，它抑制PI3Kα的激活。在临床前模型中，BBO-10203对多种肿瘤类型均有显著的肿瘤生长抑制作用，并与细胞周期蛋白依赖性激酶4/6 （CDK4/6）、雌激素受体（ER）、HER2和KRAS-G12C突变体抑制剂联合使用时显示出增强的疗效，包括在Kelch样ECH -相关蛋白1 （KEAP1）和丝氨酸/苏氨酸激酶11 （STK11）突变的肿瘤中。值得注意的是，这些抗肿瘤作用不诱导高血糖，因为胰岛素信号不依赖于RAS介导的PI3Kα激活来促进葡萄糖摄取。
附：英文原文
Title: BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction
Author: Dhirendra K. Simanshu, Rui Xu, James P. Stice, Daniel J. Czyzyk, Siyu Feng, John-Paul Denson, Erin Riegler, Yue Yang, Cathy Zhang, Sofia Donovan, Brian P. Smith, Maria Abreu-Blanco, Ming Chen, Cindy Feng, Lijuan Fu, Dana Rabara, Lucy C Young, Marcin Dyba, Wupeng Yan, Ken Lin, Samar Ghorbanpoorvalukolaie, Erik K. Larsen, Wafa Malik, Allison Champagne, Katie Parker, Jin Hyun Ju, Stevan Jeknic, Dominic Esposito, David M. Turner, Felice C. Lightstone, Bin Wang, Paul M. Wehn, Keshi Wang, Andrew G. Stephen, Anna E. Maciag, Aaron N. Hata, Kerstin W. Sinkevicius, Dwight V. Nissley, Eli M. Wallace, Frank McCormick, Pedro J. Beltran
Issue&Volume: 2025-06-12
Abstract: 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.
DOI: adq2004
Source: https://www.science.org/doi/10.1126/science.adq2004