Tyson Rietz
Emmanuel College (Boston)
Stephen Fesik lab
Immuunotherapy is being recognized as a key therapeutic modality to treat cancer and represents one of the most exciting treatments for the disease. My project focuses on the design and development of small-molecule inhibitors of the immunotherapeutic targets TIGIT and Tim-3. To achieve this goal, I am using a fragment-based drug discovery approach pioneered in the Fesik Lab dubbed 'SAR by NMR' that is capable of identifying weakly binding drug fragments. Once our fragment-based screen identifies chemical fragments that bind to 'subpockets' on the target protein's binding surface, the 3-dimensional structure of the protein bound to the drug fragments is determined with NMR spectroscopy or X-ray crystallography. The 3-dimensional structures provide a picture of how the fragments fit into the protein's binding site – and how they might be linked together. The fragments can then be assembled into a larger molecule that better fills up the target protein's binding pocket and consequently increases binding affinity.