Sulfonylurea to treat Cantu syndrome (CantuTreat)

The CantuTreat project aims to develop a novel therapeutic approach in treatment of Cant syndrome. Cant syndrome is a rare genetic disorder, affecting a small number of patients suffering from multiple symptoms including hypertrichosis, lymphedema, distinctive facial features and cardiac abnormalities. Cant syndrome is caused by dominant gain-of-function mutations in the ATP- dependent potassium channel. The IKATP potassium channel is a known pharmaceutical target: pharmaceutical correction of these channels by sulfonylurea drugs result in a nearly complete cure of patients with neonatal diabetes. CantuTreat brings together an international, multidisciplinary consortium to investigate the molecular and structural mechanisms of this rare disease and to develop a cost-effective treatment. In this network the objectives of the Weinzinger lab are: Structural characterization of Cant associated mutations in the IKATP channel Structural insights into the binding site and mode of action of blockers Computer simulations are well suited to gain in depth structural insights into gating perturbations of IKATP, resulting from single-point mutations. Close collaboration of research partners facilitates experimental validation of modeling data. Further, experimental results will be directly fed into theoretical models. From these studies we expect a better understanding of the function of the IKATP channel and improved possibilities for drug development, facilitated by in depth knowledge of the binding site. Further, this research serves as basis for compound optimization. The unique combination of experts in this multidisciplinary consortium with expertise in in silico, in vitro and in vivo methods, provides a clear and strategic advantage towards successful accomplishment of this innovative project.

The development of new therapeutic approaches to treat rare hereditary diseases represents a major challenge for the pharmaceutical industry. In this project, the extremely rare disease Cant syndrome was investigated. This disease is caused by different point mutations in the ATP-dependent potassium channel KATP. Clinical features of this disease include hypertrichosis (excessive hair growth), lymphedema, osteochondrodysplasia (bone tissue disorder) and cardiomegaly (enlargement of the heart muscle). At the beginning of the project we hypothesized that sulfonlyureas, a drug class that has been successfully used to treat diabetes for many years, might also constitute a promising therapeutic approach for the treatment of Cant patients, as the defective proteins are closely related. A major goal of this project was therefore to analyze the efficacy of the known sulfonylurea drug glibenclamide on selected Cant causing mutations. In collaboration with Dutch research groups, we were able to show that this drug can indeed effectively regulate the overactivity of certain defective KATP channels (Houtman et al, 2019). However, it has also been shown that sulfonylureas are not effective for all point mutations (Cooper et al, 2017). Therefore, another important aspect of this project was the search for new drugs, which, due to the extreme rarity of the disease, should constitute approved drugs (for other applications). Using a new computer-based approach, we were able to filter out new drugs that are already approved on the market, which can inhibit defective KATP channels and thus offer a promising approach for new therapies (Chen et al, 2019).