Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizers

Abstract

Targeted protein degradation and stabilization are promising therapeutic modalities due to their potency and versatility. However, only few E3 ligases and deubiquitinases have been harnessed for this purpose. Moreover, there may be other protein classes that could be exploited for protein stabilization or degradation. Here, we used a proteome-scale platform to identify hundreds of human proteins that can promote the degradation or stabilization of a target protein in a proximity-dependent manner. This allowed us to comprehensively compare the activities of human E3s and deubiquitinases, characterize non-canonical protein degraders and stabilizers, and establish that effectors have vastly different activities against diverse targets. Notably, the top degraders were more potent against multiple therapeutically relevant targets than the currently used E3s CBRN and VHL. Our study provides a functional catalogue of effectors for targeted protein degradation and stabilization and highlights the potential of induced proximity screens for discovery of novel proximity-dependent protein modulators.