Structure-guided de novo design of molecules that selectively target EWS-FLI1
Ewing sarcoma is an aggressive cancer that primarily affects children and adolescents. There are no targeted therapies for Ewing sarcoma and the prognosis upon relapse or metastasis is bleak for most patients. The major vulnerability of Ewing sarcoma, the fusion protein EWS::FLI1, has proven to be undruggable despite heroic efforts by many research groups. We are proposing an entirely novel approach that will uncover new, high-resolution structural insights about behavior and properties of the EWS::FLI1 fusion. We will then combine these observations with data from our proteomic studies to improve the design of molecules that interact selectively bind EWS::FLI1. We will incorporate our experimental approaches with leading-edge computer-aided optimization techniques to guide and improve our designs. The over-arching goals of our approach is to use these molecules to entice the patient’s cellular machinery to selectively target and degrade EWS-FLI1.
Project Goal:
The goal of our project is to provide proof that selective targeting of EWS::FLI1 is feasible and achievable. The preliminary data supporting our premise demonstrates that a detailed (atomic) level understanding of how EWS::FLI1 selects and binds natural ligands opens the possibility of designing highly selective binding partners. We therefore aim to elucidate the rules that govern EWS::FLI1 interactions with it native ligands and use this information to improve the selectivity of a series of designed molecules. A parallel effort within the proposal will seek to determine if computational design approaches and directed evolution can develop molecules that are as (or more) selective than natural ligands. Together these efforts will advance our long term project goals of selective targeting and directed degradation of EWS::FLI1.
