Molecular glues that facilitate RAS binding to PI3Kα promote glucose uptake without insulin

• 成果类型: Article
• 署名作者: Terayama, Koji; Furuzono, Shinji; Fer, Nicole; Yan, Wupeng; Young, Lucy C.; Czyzyk, Daniel J.; Goldstein de Salazar, Ruby; Sasaki, Masato; Uozumi, Akihiro; Konishi, Masahiro; Kanda, Shoichi; Sogawa, Yoshitaka; Yamaguchi, Mitsuhiro; Tsuji, Takashi; Kuroyanagi, Junichi; Hayashi, Mayumi; Ogura, Yuji; Simanshu, Dhirendra K.; Kubota, Kazuishi; Tanaka, Jun; McCormick, Frank
• 署名单位: Daiichi Sankyo Company Limited; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; Daiichi Sankyo Company Limited; Daiichi Sankyo Company Limited; Daiichi Sankyo Company Limited
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13173
• DOI: 10.1126/science.adr9097
• 发表日期: 2025-07-24
• 页码: 402-408
• 关键词: cell-proliferation; structural insights; signaling pathways; mutations

摘要

While exploring strategies to control blood glucose concentrations in diabetes, we identified so-called molecular glues D223 and D927 that promote glucose uptake in the absence of insulin. They act by increasing the binding affinity of phosphoinositide 3-kinase alpha (PI3K alpha) catalytic subunit p110 alpha to canonical small guanosine triphosphatase RAS proteins and to RRAS, RRAS2, and MRAS by three orders of magnitude. The compounds bind to the RAS-binding domain of p110 alpha, stabilizing the secondary structures of the PI3K alpha in a RAS-binding conformation and forming direct interactions with RAS residues tyrosine-40 and arginine-41. In vivo, D927 mimicked the effects of insulin: It rapidly lowered blood glucose concentrations, enhanced glucose metabolism in normal and Zucker fatty rats, and improved hyperglycemia in models of type 1 and type 2 diabetes, even in insulin-deficient diabetic animals.