With more than 600 E3 ligases encoded in the human genome, there is a significant need to expand the number of utilized E3 ligases for HDAC degradation. Furthermore, unlocking specific E3 ligases with dedicated tissue or cell-type specificity holds great potential for achieving degradation in the desired tissue. Likewise, targeting tumor-or disease-enriched E3 ligase could enable the development of more refined and selective degraders. Expanding the use of new E3 ligases can also help to target new tumor entities; for example, it has been shown that the sensitivity pattern of tested tumor cell lines to PROTACs changes by switching from CRBN to VHL. However, ligands for both E3s come with some limitations, as thalidomide is associated with teratogenicity and stability issues, while the VHL ligands increase molecular weight and topological polar surface area, which can be challenging for oral bioavailability. Using E3 ligases which degrade tumor suppressor-proteins can have additional anticancer effects. For example, mouse double minute 2 homolog (MDM2) recruitment for TPD leads to a stabilization of p53 and p21 is substrate of the E3 ligase DCAF11. Lately, the range of E3 ligases used in TPD has expanded. For example, ligands for Fem-1 homolog B (FEM1B), Ring Finger Protein 4 (RNF4), Ring Finger Protein 114 (RNF114), DDB1-and CUL4-associated factor 11 (DCAF11), and DDB1-and CUL4-associated factor 16 (DCAF16) have been utilized in TPD strategies. These ligands share an electrophilic warhead to engage the E3 ligase, resulting in a pseudo-binary complex of E3 ligase, covalently bound PROTAC, and POI. This results in simpler kinetics, as the covalent construct of E3 ligase and PROTAC only needs to recruit a new POI molecule for polyubiquitination.