Looking forward, the prospect of using a cell permeable, covalent E3 recruiter looks particularly attractive for PROTAC degrader design. SOCS2 is a substrate receptor for a Cullin RING ligase complex, and specifically a Cullin5 complex (CRL5 SOCS2 ), hence should be amenable to be hijacked by targeted protein degraders such as PROTACs. Covalent engagement of the E3 ligase can bring advantages to the substoichiometric catalytic mode of action of the degrader molecule, including simplifying the PROTAC binding equilibrium such that only a single step may occur as the ternary complex dissociates to E3-PROTAC and target protein, but not at the other end as is the case with non-covalent PROTACs . These potential benefits of covalency at the E3 ligase can only be realised in full if the half-life of the E3 protein is long enough, such that the covalent modification can be maintained and sustained with time without the engaged compound being rapidly consumed inside the cell. Using cycloheximide treatment to block protein resynthesis, we showed that SOCS2 has a half-life longer than 24 h (Supplementary Figure ), thereby reassuring that MN714 could offer a kinetic advantage when used as E3 recruiter or handle for PROTACs. PROTACs have provided a new pharmacological paradigm of targeted protein degradation, with over a dozen compounds today in clinical trials, and many more in pre-clinical development, that degrade a variety of different targets against different diseases . Resistance mechanisms already observed for VHL and CRBN, the most widely hijacked E3 ligases with PROTAC degraders, converge in the loss or missense mutations in E3 ligase components, including the substrate adaptors . These observations motivate the search for novel E3 ligase recruiters, as expanding the reach of degraders to new E3 ligases could circumvent such innate or acquired resistance. Since SOCS2 is a substrate receptor for CRL5 , it could open up differentiative biology relative to VHL and CRBN, which are substrate adaptors of CRL2 and CRL4 complexes instead, respectively. Further differences include their subcellular localization e.g. SOCS2 is exclusively cytoplasmic while VHL and CRBN are more ubiquitously expressed, including in the nucleus, and the more tissuerestricted expression profiles of SOCS2 compared to VHL and CRBN, as evident from inspection of protein expression data e.g. from ProteomicsDB (). In these regards, work is ongoing in our laboratory to establish proof-of-concept for utilizing the SOCS2 binding ligands developed herein into fast and potent PROTAC degraders and hence explore utility of SOCS2 as new E3 ligases for targeted protein degradation.