Balancing FOXO1 inhibition opens up a new target in diabetes

Finding effective approaches to restoring insulin sensitivity without causing unwanted effects, such as increased lipid levels and weight gain, has been a scientific challenge for years. Mechanistic studies are starting to unravel FOXO1 biology to tackle this unmet need.

In collaboration with Columbia University Medical Center, our scientists in the IMED Biotech Unit at AstraZeneca have started to understand the complexities of FOXO1 biology as a possible diabetes drug target to reduce blood glucose levels.

The findings, published in the recent issue of Cell, describe how the team has identified a novel mode of action for FOXO1, raising the possibility to develop novel selective inhibitors to dial-out the adverse effects of known insulin sensitizers.

Excessive glucose production by the liver is a hallmark of diabetes. Insulin inhibits the production of glucose by suppressing the ability of FOXO1 to activate the glucose-6-phosphatase gene. This makes FOXO1 inhibition a desirable treatment target in diabetes. However, FOXO1 also suppresses triglyceride production via repression of the glucokinase gene. Thus, complete FOXO inhibition is liable to increase liver fat. This dual action has precluded the development of FOXO1 inhibitors as insulin sensitizers without affecting triglyceride production.

This leaves us with a fine balancing act between inhibiting glucose synthesis and potentially increasing the risk for developing cardiovascular disease, an endpoint of altered lipid metabolism. What we needed to understand is how the two FOXO1-mediated mechanisms differ, so we could identify selective inhibitors

Daniel Lindén CVMD Principal Scientist, IMED Biotech Unit

Through AstraZeneca’s long-standing collaboration with Professor Domenico Accili, MD, a world-leading expert in diabetes at Columbia University Medical Centre, the team has uncovered the mechanism. “By interrogating the biological activity of FOXO1 in a number of cellular models [developed in Professor Accili’s lab], we identified that FOXO1 requires the cofactor SIN3A to switch off the lipogenesis and production of triglycerides via glucokinase suppression. This meant we could hypothesise that if glucose-6-phosphatase could be switched off without affecting glucokinase, we would achieve the desired outcome to suppress glucose production in the liver without causing increased triglyceride accumulation.” Daniel Lindén added.

Accili added, “This work represents a breakthrough in targeting a biologically validated protein in the insulin signalling pathway with a degree of specificity heretofore unheard of. There were many challenges along the road, for example designing the assay screen, identifying the nature of the FOXO partners, as well as suitable endpoints for analyses. And many challenges, arguably even greater, remain. Nonetheless, I am very proud of the work we did with our colleagues at AstraZeneca.”

Taking this finding, researchers in IMED Discovery Sciences set about generating high throughput assays to screen for FOXO1 inhibitors. “We whittled down over 1 million compounds to only 13, which we monitored for hepatic glucose production and de novo lipogenesis. From these assays, we identified the first selective inhibitor of FOXO1-mediated hepatic glucose production without effects on lipogenesis.” said Anders Johansson, CVMD Chemistry Team Leader, IMED Biotech Unit.

Whilst these compounds are not optimised for in vivo utilisation, they offer a foundation for further research. This work also formed part of Professor Accili’s Banting Medal lecture at the American Diabetes Association’s 77th Scientific Sessions, in June 2017.

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