Inhibitor mediated protein degradation: Commentary

摘要

The discovery of drugs that cause the degradation of their target proteins has been largely serendipitous. Here we report that the tot-butyl carbamate-protected arginine (Boc3Arg) moiety provides a general strategy for the design of degradation-inducing inhibitors. The covalent inactivators ethacrynic acid and thiobenzofurazan cause the specific degradation of glutathione-S-transferase when linked to Boc3Arg. Similarly, the degradation of dihydrofolate re-ductase is induced when cells are treated with the noncovalent inhibitor trimethoprim linked to Boc3Arg. Degradation is rapid and robust, with 3O°/o-8O?/o of these abundant target proteins consumed within 1.3-5 h. The proteasome is required for Boc3Arg-mediated degradation, but ATP is not necessary and the ubiquitin pathways do not appear to be involved. These results suggest that the Boc3Arg moiety may provide a general strategy to construct inhibitors that induce targeted protein degradation.