Molecular glue to fix disease
Emira Visser defended her thesis at the Department of Biomedical Engineering on June 27th.
Proteins are essential macromolecules responsible for regulating cellular processes. Small changes in protein-protein interactions (PPIs) can lead to serious diseases. Although inhibition of PPIs is already widely used, the strategy of stabilizing proteins with molecular glues remains underexplored. In her PhD thesis, Emira Visser investigated the design and optimization of 14-3-3 molecular glues for the treatment of breast cancer and type 2 diabetes. These molecular glues have promising potential as new drugs.
Visser, researcher in the Chemical Biology group, used the protein "14-3-3" as a basis to characterize bottom-up strategies for designing molecular glues. 14-3-3 is a small protein that binds many interaction partners and is therefore involved in almost every disease. This protein provides the opportunity to study hundreds of PPIs in a quantitative and comparative manner. The first goal of the thesis was to develop and optimize molecular glues for the interaction of 14-3-3 with the estrogen receptor-alpha (ERα) and carbohydrate response element-binding protein (ChREBP). These molecular glues have potential as new drugs for the treatment of breast cancer and type 2 diabetes.
Inhibition of breast cancer cell growth
The developed molecular glues were then tested for their effect on the formation of breast cancer and type 2 diabetes. Stabilizing 14-3-3 with ERα was found to inhibit breast cancer cell growth. In addition, cancer variants that showed resistance to first-line treatments were suppressed by the new treatment. Stabilizing 14-3-3 with ChREBP was found to inhibit the activity of ChREBP in beta cells. This is important because type 2 diabetes is associated with overactive ChREBP variants, leading to beta cell death. Stabilizing ChREBP with 14-3-3 suppressed ChREBP activity and allowed beta cells to be maintained under high glucose conditions.
Visser's research provides an in-depth exploration of the development and application of 14-3-3 molecular adhesives. The identified and optimized molecular glues were found to be able to suppress breast cancer growth and treat type 2 diabetes. These findings offer new prospects for alternative treatment options in these diseases. Although further studies and clinical applications are needed, Visser's research illustrates the potential of molecular glues as a promising approach in medicine.
Title of PhD thesis: Evolution of 14-3-3 molecular glues: From fragment hits to cellularly active leads (this is under embargo until December 27, 2023)
Supervisors: Luc Brunsveld and Wilbert Zwart