Development of Ubiquitin-Independent Degraders

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.