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

Area of Science:

• Biochemistry
• Pharmacology
• Endocrinology

Background:

• Diabetes mellitus is characterized by hyperglycemia due to impaired glucose regulation.
• Current diabetes therapies often rely on insulin or aim to enhance its action.
• Novel strategies are needed to control blood glucose concentrations, particularly in insulin-deficient states.

Purpose of the Study:

• To identify novel compounds that promote glucose uptake independently of insulin.
• To elucidate the molecular mechanism by which these compounds exert their glucose-lowering effects.
• To evaluate the efficacy of these compounds in preclinical models of diabetes.

Main Methods:

• Identification and characterization of molecular glues D223 and D927.
• Biochemical assays to assess the binding affinity of PI3Kα to RAS proteins.
• Structural analysis of compound binding to the PI3Kα RAS-binding domain.
• In vivo studies in normal and diabetic rodent models (type 1 and type 2).

Main Results:

• Molecular glues D223 and D927 were identified, promoting glucose uptake without insulin.
• These compounds significantly increased the binding affinity of PI3Kα to RAS proteins.
• Compound D927 demonstrated insulin-mimetic effects in vivo, rapidly lowering blood glucose.
• D927 improved hyperglycemia in both type 1 and type 2 diabetes models, including insulin-deficient animals.

Conclusions:

• Molecular glues D223 and D927 represent a novel class of compounds for glucose regulation.
• Their mechanism involves enhancing PI3Kα-RAS interaction, leading to insulin-independent glucose uptake.
• These findings offer a potential new therapeutic avenue for managing diabetes, especially in cases of insulin deficiency.