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.