PROteolysis TArgeting Chimeras (PROTACs) have gained considerable attention as a new modality in drug discovery. However, the development of PROTACs has been mainly focused on CRBN (Cereblon) and VHL (van Hippel-Lindau Ligase) ligands. The considerable size of the human E3 ligase family, newly developed E3 ligase ligands, as well as the favorable druggability of some E3 ligase families hold the promise that novel degraders with unique pharmacological properties will be designed in the future using this large target space. Here, we developed a workflow for the evaluation of E3 ligand efficiency for PROTAC development and the corresponding “degradable” target space using broad-spectrum kinase inhibitors and the well-established VHL ligand VH032. Our study revealed VH032 linker attachment points that are highly efficient for kinase degradation and highlighted some of the pitfalls when using protein degradation as a readout. For instance, cytotoxicity was identified as a major mechanism leading to PROTAC- and VHL-independent kinase degradation. The combination of E3-ligand negative controls, kinase parent compounds and other tool compounds such as neddylation and proteasome inhibitors was essential to distinguish between VHL-dependent and -independent kinase degradation events. We hope that this study will provide a blueprint for future evaluation of the efficacy of new E3 ligand systems for degrader development.