In the latest issue of Cell Chemical Biology, PROXIDRUGS scientists Varun Shah and Ivan Đikić comment on an article published by Simpson et al from MRC's Protein Phosphorylation & Ubiquitiylation Unit at University Dundee. The work of Simpson and colleagues shows that accessibility of the target protein by PROTAC-
mediated degradation varies depending on subcellular localization of the target. The commentary points out that it would be highly interesting to learn more about diffusibility of PROTACs within cells – one of the many challenges in the field that need to be explored yet.
Engaging organelle-specific E3s to degrade a specific targets may even help to reduce off-target effects. As Shah and Đikić summarize, this work once more raises the question as to what extent the global proteome can be targeted with just a small selection of E3 ligases bein available yet. Surely the exploiting of additional E3 ligases, that show tissue-specific expression or context-dependent regulation could significantly expand the therapeutic application space of PROTACs.