Targeted protein degradation (TPD), induced by enforcing target proximity to an E3 ubiquitin ligase using small molecules has become an important drug discovery approach for targeting previously undruggable disease-causing proteins. However, out of over 600 human E3 ligases, just over 10 E3 ligases are currently utilised for TPD. Here, using the Affinity-directed PROtein Missile (AdPROM) system, in which an anti-GFP nanobody was linked to an E3 ligase, we screened over 30 different E3 ligases for their ability to degrade 4 target proteins, K-RAS , STK33, ß-Catenin and FoxP3, which were endogenously tagged with GFP. Several new E3 ligases, including CUL2 diGly receptor KLHDC2, emerged as effective degraders, suggesting that these E3 ligases can be taken forward for the development of small molecule degraders, such as PROteolysis TArgeting Chimeras (PROTACs). As a proof-of-concept, we demonstrate that a KLHDC2-recruiting peptide-based PROTAC connected to choloroalkane is capable of degrading HALO-GFP protein in cells.