Diabetes type 1 is characterized by destruction of β-cells leading to loss of endogenous insulin production and daily insulin injections are required to control blood glucose levels. An alternative treatment would be to restore insulin secretion by regeneration of β-cells. The forkhead box class O subfamily of forkhead transcription factors are involved in gene expression related to cellular processes such as proliferation and differentiation. The FoxO1 transcription factor regulates many aspects of pancreatic β-cell function and it has been shown that ablation of FoxO1 gene in Neurog3+ enteroendocrine progenitor cells restores insulin production by development of insulin positive intestinal cells.We were interested in identifying novel selective small molecule inhibitors of FoxO1 to investigate pharmacological FoxO1 inhibition as a method to re-establish insulin production. Several chemical series were identified through high throughput screening (HTS). Additional optimization of FoxO1 selectivity and DMPK properties led to the discovery of novel FoxO1 inhibitors suitable for in vivo concept testing.

Discovery of novel FoxO1 inhibitors for the treatment of diabetes

2019 Fall National Meeting

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