Drugging the Undruggable: Hacking the cell's proteolytic machinery to develop new therapeutics (2022-02-25)

Abstract

Modern pharmacology relies upon the stoichiometric interaction between a drug and its target.This paradigm has served humanity and animals well for over 100 years to treat disease and improve lives. However, not all disease-associated, protein targets are readily amenable to this approach. Recently, a new tactic has been developed to target proteins of interest for proteolytic degradation using the cell's ubiquitin-proteasome, lysosome, or macroautophagy system. The advantages of proteolytic degradation compared to small molecule inhibitors include: 1) the capability of targeting proteins without a traditional enzymatic or allosteric binding site, 2) inhibiting not only the catalytic activity but also the scaffolding function of a protein, 3) a catalytic rather than stoichiometric interaction with the target, and 4) a greater and more prolonged inhibition of protein function.Several molecules are now being tested in clinical trials and have shown that not only is this approach feasible but also can provide clinical benefit.