Identification of Boc2Lys-Linked Ethacrynic Acid and Its Analogues As Efficient Glutathione S-Transferase Degraders

Abstract

Targeted protein degradation has been emerging as a promising strategy for drug design and a useful tool for the research of intracellular protein function by specifically downregulating the protein level via promoted degradation. Aside from proteolysis targeting chimeras (PROTAC) that utilize a specific E3 ligase ligand as a tag to recruit polyubiquitin onto the targeted protein and subsequently induce degradation, Boc₃Arg was also reported an efficient tag to induce degradation through directly localizing the protein to the 20S proteasome. Based on the similarity of Boc₂Lys and Boc₃Arg, we identified that Boc₂Lys also efficiently induced targeted protein degradation, taking glutathione S-transferase as an example. We found that Boc₂Lys-linked ethacrynic acid was able to dose-dependently downregulate the target protein in a mechanism distinct to Boc₃Arg.