2. Academic Validation
  3. Molecular glues that facilitate RAS binding to PI3Kα promote glucose uptake without insulin

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

  • Science. 2025 Jul 24;389(6758):402-408. doi: 10.1126/science.adr9097.
Koji Terayama # 1,  Shinji Furuzono # 1,  Nicole Fer 2,  Wupeng Yan 2,  Lucy C Young 3,  Daniel J Czyzyk 2,  Ruby Goldstein de Salazar 3,  Masato Sasaki 4,  Akihiro Uozumi 1,  Masahiro Konishi 1,  Shoichi Kanda 1,  Yoshitaka Sogawa 1,  Mitsuhiro Yamaguchi 5,  Takashi Tsuji 5,  Junichi Kuroyanagi 5,  Mayumi Hayashi 6,  Yuji Ogura 6,  Dhirendra K Simanshu 2,  Kazuishi Kubota 6,  Jun Tanaka 1,  Frank McCormick 2 3
Affiliations

Affiliations

  • 1 Cardiovascular Metabolic Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
  • 2 National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 3 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
  • 4 Organic and Biomolecular Chemistry Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
  • 5 Medicinal Chemistry Research Laboratory, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
  • 6 Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
  • # Contributed equally.
PMID: 40705882 DOI: 10.1126/science.adr9097
Abstract

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 α (PI3Kα) catalytic subunit p110α 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 p110α, stabilizing the secondary structures of the PI3Kα 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.

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