Selective FOXO1 inhibitors for the treatment of insulin-dependent diabetes

This technology is an oral, small-molecule therapeutic that selectively inhibits the transcription factor FOXO1 to reprogram intestinal cells into insulin-producing cells, providing a non-invasive treatment option for Type 2 Diabetes.

Unmet Need: Non-invasive, long-lasting therapy for insulin-dependent diabetes

Type 2 diabetes affects over 23 million people in the U.S. and is a leading cause of morbidity and mortality worldwide. Current treatment strategies, such as injectable insulin and GLP-1 analogs, are invasive and often fail to address the underlying loss of functional beta cells. Widely prescribed oral drugs like metformin can have gastrointestinal and metabolic side effects, and do not restore insulin production capacity. There remains a strong clinical need for non-invasive, durable therapies that restore or replace beta cell function to maintain glycemic control without daily injections.

The Technology: Small molecule FOXO1 inhibitors for diabetes therapy

This technology describes a novel class of pyrazole-based small molecules that selectively inhibit the FOXO1 transcription factor in the gastrointestinal tract. FOXO1 inhibition triggers conversion of enteroendocrine cells into insulin-producing cells, functionally replacing damaged or deficient pancreatic beta cells. This platform represents a promising oral therapeutic approach for insulin-dependent diabetes, combining ease of administration with potential long-term restoration of endogenous insulin production.

The compounds have been synthesized and tested in vitro, demonstrating selective inhibition of FOXO1 and induction of insulin expression in gut-derived cells.

Applications:

• Treatment for type 2 diabetes and related metabolic disorders
• Therapeutic reprogramming of gut cells for insulin replacement
• Research tool for studying FOXO1 signaling and cell fate reprogramming
• Drug discovery framework for other metabolic and endocrine diseases

Advantages:

• Non-invasive oral therapy for insulin-dependent diabetes
• Selective FOXO1 inhibition to restore endogenous insulin production
• Potential for long-term efficacy
• Potential for reduced treatment burden
• Complementary to existing glucose-lowering drugs

Lead Inventor:

Domenico Accili, M.D.

Patent Information:

Patent Pending (US 20220185797)

Related Publications:

• Kitamoto T, Lee YK, Sultana N, Watanabe H, McKimpson WM, Du W, Fan J, Diaz B, Lin HV, Leibel RL, Belvedere S, Accili D. “Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes.” Mol Metab. 2022 Dec; 66: pp.101624.

• Lee YK, Du W, Nie Y, Diaz B, Sultana N, Kitamoto T, Leibel RL, Accili D, Belvedere S. “Single-agent FOXO1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice.” Mol Metab. 2022 Oct 22; 66: pp.101618.

Tech Ventures Reference:

• IR CU19186

• Licensing Contact: Cynthia Lang