Targeted protein degradation (TPD) via molecular glues or PROTACs (Proteolysis-targeting chimeras) is an up-and-coming drug modality holding promise to drug the “undrugabbles.” Further expanding the collection of targetable E3 ligases for TPD, we report the discovery of ligands targeting the C-END degron receptor KLHDC2. Utilizing the BRD targeting ligand JQ1 as a test case, we demonstrate that KLHDC2 ligands can be readably converted to PROTACs for TPD, enabling remarkable isoform selectivity and cooperative ternary complex formation with BRD3BD2. We demonstrate that formation of cooperative neo-substrate ternary complexes with KLHDC2 is largely reliant on the exit vector emanating from the ligand bound deep in KLHDC2s U-shaped di-Gly binding pocket. Additionally, we establish the feasibility of generating selective ligands targeting KLHDC2, as the ligands developed here are unable to target the related binding pockets of the KLH family members KLHDC1, KLHDC3, or KLHDC10. Finally, we establish that KLHDC2 targeting ligands can effortlessly overcome the degron-mimic mediated tetramerization and inhibition of KLHDC2-EloB/C and that pro-drug variants can overt cellular permeability limitations of small molecules retaining acid binding moieties. In sum, our study confirms prior observations suggesting KLHDC2 might be amendable to TPD and establish principles to guide PROTAC development targeting C-END E3 ligases.