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

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. Editor's summary: Phosphoinositide 3-kinase (PI3K) has important roles in receptor signaling that control many processes, including cell growth and metabolism. Two papers in this issue target PI3K signaling in different ways and for different effects (see the Perspective by Solinas). Simanshu et al. developed a small molecule that inhibits activation of PI3Kα by members of the Ras family of small guanosine triphosphatases. The compound effectively inhibited tumor growth in mice, but because insulin signaling does not require Ras proteins, it does so without hyperglycemic side effects. It was also effective against tumors promoted by excessive human epidermal growth factor receptor activity. Terayama et al. describe small-molecule PI3Kα activators that could regulate blood glucose concentrations in rat muscle cells in culture without the hormone insulin. These compounds functioned in an unusual manner by enhancing the binding of rat sarcoma (RAS) family proteins to PI3Kα by nearly three orders of magnitude. Their effectiveness in ameliorating hyperglycemia in a rat model of diabetes indicates that they may prove useful as therapeutic agents for the control of blood glucose without the use of insulin. —L. Bryan Ray [ABSTRACT FROM AUTHOR]