Project Details
Projekt
The dual leucine-zipper kinase (DLK) as novel drug target for antidiabetic therapy – target validation as well as structure-based design, synthesis and biological evaluation of DLK inhibitors
Subject Area
Pharmacology
Pharmacy
Pharmacy
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 563181121
Diabetes mellitus is one of the most increasing diseases worldwide and is a major risk factor for the pathogenesis of cardiovascular diseases, which are still the most prevalent cause of death in Germany. Obesity is pivotal for the development of type 2 diabetes mellitus (T2DM) but it is the loss of function and mass of the insulin producing β-cells within the islets of Langerhans in the pancreas precipitating T2DM with elevated blood glucose levels. Thus, the protection of β-cells should prevent or at least retard the pathogenesis of T2DM. However, this goal is still not achieved by nowadays blood glucose lowering combination therapies. Our own data from the β-cell line HIT, isolated murine islets and mice suggest that the dual leucine-zipper kinase is a novel drug target for antidiabetic therapy. We propose that inhibition of DLK protects β-cells despite diabetogenic conditions and prevents T2DM. Using computational methods, we identified five potential DLK inhibitors in a structure-based virtual screening. The first aim of this project is to investigate whether β-cell-selective deletion of Dlk in the db/db-mice, a well-known diabetes model, prevents the development of diabetes and associated cardiovascular disease. The second aim is to evaluate our DLK inhibitors regarding their antidiabetic and toxic effects. Furthermore, novel promising compounds will be identified using computer-based methods among others. Subsequently, these compounds will be investigated by structural biological, biochemical and cell biological methods to verify their suitability as lead structures. Finally, these lead structures will be optimized concerning their affinity and selectivity towards DLK.
DFG Programme
Research Grants
