Targeting a new signaling cascade with specific inhibitors for obesity treatment – GreatObTreat

Obesity is the most serious public health problem in recent decades. It is associated with multiple comorbidities, such as type 2 diabetes or myocardial infarction. Treatment options remain quite limited: on the one hand, surgical interventions with good weight loss results, but with significant and irreversible complications; on the other hand, the use of therapeutic agents with limited weight loss and significant side effects. It is therefore essential to identify new targets and new therapeutic agents for the treatment of this disease. In this project we identify a new signaling pathway controlling body weight. The inhibition of this cascade by the knockout of one of its components results in a significant loss of body fat in mice without any other side-effect observed up to eight months of treatment. We additionally demonstrate that this pathway can be druggable and provide specific inhibitors. Remarkably, the injection of these compounds in mice has a significant slimming effect that could be from two- to four-fold higher than classical therapies used in humans. This effect is also in obese mice. Data indicate that this cascade could be a highly interesting new target for obesity treatment. However, before considering this pathway for anti-obesity treatment, and in order to evaluate putative side-effects, it is first mandatory to identify the target(s) mediating this phenotype. Moreover, hit-to-lead optimization of our drugs is necessary to obtain inhibitors with high specificity, high biological activity and pharmacokinetic properties allowing per os administration. Therefore, the main objectives of these project are: (1) the identification of the targets of this signaling pathway mediating its slimming phenotype, (2) the synthesis of new drug analogs with improved activity and specificity without site-effects and (3) the development of first pilot preclinical studies devoted to assess the putative toxicity and to find minimal therapeutic drug concentration.