MICA: Identifying inhibitors of ectonucleotide pyrophosphatase/phosphodiestserase 6 (ENPP6) for the treatment of obesity and cardiometabolic disease

Obesity is a burgeoning global health problem. Accumulation of fat, in particular around the internal organs (abdominal), increases the chances of diabetes and fatty liver and heart disease. These conditions lead to long-term medical interventions and lowered life expectancy. Although it is well-recognised that obesity is a major factor in developing cardiometabolic disease, there are very few well validated therapeutic targets from which new medicines can be developed. Moreover, there no drugs that ameliorate unfavourable abdominal fat distribution.
We have discovered that rare individuals have changes in a specific gene that leads to reduced accumulation of abdominal fat. Further studies in mice that lack this gene showed they have reduced abdominal fat and that they are resistant to the development of type 2 diabetes and fatty liver disease. These results suggest that blocking the gene will be beneficial for the treatment of obesity and its related diseases.. We now seek to find new medicines that specifically block the protein and that will ultimately help patients with metabolic disease.

Obesity is the fastest growing public health problem in the developed world. Moreover, visceral fat accumulation associates with a pronounced risk for cardiometabolic mortality. There is paucity of well validated targets in discovery and clinical development, and no targets that ameliorate unfavourable fat distribution in concert with gross adiposity.
We used genome wide association analysis, initially in a population isolate (Orkney), to uncover human DNA variants associated with reduced visceral adiposity in the gene ENPP6 that encodes a novel and druggable enzyme target (ENPP6). Reduced visceral fat and improved metabolic profiles (lower liver and plasma triglycerides, improved glucose tolerance) have been recapitulated in Enpp6-/- mice, supporting the concept that ENPP6 inhibition is a novel and viable therapeutic strategy.
Following funding from the MRC Confidence in Concept fund we have generated an expanded screening cascade for the discovery of selective ENPP6 inhibitors, including a robust fluorescent primary screening assay in 384-well format and relevant gene-family selectivity assays. We now seek to identify potent and selective inhibitors of ENPP6 as starting points for further optimisation towards the generation of a new medicine.

Our proposal focuses on a new therapeutic target for the treatment of obesity and associated cardiometabolic complications. We seek to identify inhibitors of our target enzyme which will be further optimised to develop a new medicine. If successful, our work will directly impact patients with metabolic disease and their families. This work will also impact on researchers working within the metabolic disease field as some of the tool compounds developed during the project will be made available and data released through publication in internationally leading journals.
The research team will engage with leading academics, clinicians and industry partners throughout the project to maximise its impact. We will also engage with the public through print and online media. Results will be disseminated at conferences and through peer-reviewed publication.
This is a translational project which will have a commercial focus. Commercial opportunities will be pursued either via early partnering with industry or though the creation of a spin-out company. The applicants are well placed to deliver on this objective given their significant and sustained interactions with major pharma and biotech concerns. Establishing a spin-out organisation will have considerable economic impact through the generation of new employment opportunities and the applicants will work closely with the relevant Technology Transfer groups in order to rigorously explore the potential for university-led company creation. Financial benefits arising from licensing opportunities will be reinvested in university and industry-led research providing a legacy and long-term impact well beyond the initial focus of this research.
We expect this project to have significant international reach. The generation of a new medicine for the treatment of obesity and associated metabolic disease will have wide-ranging public health and societal implications. Developing a new treatment for obesity will have immense impact on healthcare providers. Long-term benefits from a reduction in the cardiovascular complications of obesity will extend life and reduce strain on currently over-burdened healthcare services.