Discovery of SOCS7 as a versatile E3 ligase for protein-based degraders.

Targeted protein degradation (TPD) strategy harnesses the ubiquitin-proteasome system (UPS) to degrade a protein of interest (POI) by bringing it into proximity with an E3 ubiquitin ligase. However, the limited availability of functional E3 ligases and the emergence of resistance through mutations in UPS components restrict this approach. Therefore, identifying alternative E3 ligases suitable for TPD is important to develop new degraders and overcome potential resistance mechanisms. Here, we use a protein-based degrader method, by fusing an anti-tag intracellular antibody to an E3 ligase, to screen E3 ligases enabling the degradation of a tagged POI. We identify SOCS7 E3 ligase as effective biodegrader, able to deplete its target in various cell lines regardless of the POI's subcellular localization. We show its utility by generating a SOCS7-based KRAS degrader that inhibits mutant KRAS pancreatic cancer cells' proliferation. These findings highlight SOCS7 versatility as valuable E3 ligase for generating potent degraders.