Project Summary Degraders are chemical dimerizers that recruit a target protein (TP) to an E3 Ubiquitin (Ub) ligase. In favorable cases, this results in TP poly-Ubiquitylation and subsequent destruction by the proteasome. Degraders are difficult to develop because of the requirement that the degrader promote significant protein-protein interactions between the TP and E3 Ub ligase in such a way that a TP lysine residue is placed appropriately to attack the activated Ub molecule. Here we propose to develop a new class of degraders that will recruit TP directly to the proteasome. We anticipate that this mechanism of action will result in potent TP destruction without the need for Ubiquitylation, which, in turn, will make the development of these degraders far more straightforward.

Project Narrative This project will develop a new class of Ubiquitin-independent protein-degrading small molecules that function by recruiting target proteins directly to the proteasome. This approach is quite novel and differs from any existing degrader strategy and will greatly simplify the development of degraders. Critical to this effort will be the discovery of high-quality ligands for the 19S Regulatory Particle of the proteasome, which will be accomplished by a novel DNA-encoded library screening strategy.