BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction
- 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
2025-06-12
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 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, because insulin signaling does not depend on RAS-mediated PI3Kα activation to promote glucose uptake.