Development of High-Affinity Ligands for Human UBR2

∼ 20-40 nM and with 10-fold selectivity over UBR2's closest homologue, UBR1. High-resolution cocrystal structures (∼1.2 Å) of UBR2 in complexes with two high-affinity tripeptides revealed molecular mechanisms for their high-affinity binding. Importantly, a high-affinity UBR2 ligand effectively attenuated cancer-induced cachexia in a cellular model. Our findings demonstrate that the UBR boxes are ligandable and thus could spur interest in targeting this class of E3 ligases for developing novel therapeutic approaches for the treatment of cachexia and other illnesses.