Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets

Abstract

Traditionally, small-molecule or antibody-based therapies against human diseases have been designed to inhibit the enzymatic activity or compete for the ligand binding sites of pathological target proteins. Despite its demonstrated effectiveness, such as in cancer treatment, this approach is often limited by recurring drug resistance. More importantly, not all molecular targets are enzymes or receptors with druggable 'hot spots' that can be directly occupied by active site-directed inhibitors. Recently, a promising new paradigm has been created, in which small-molecule chemicals harness the naturally occurring protein quality control machinery of the ubiquitin-proteasome system to specifically eradicate disease-causing proteins in cells. Such 'chemically induced protein degradation' may provide unprecedented opportunities for targeting proteins that are inherently undruggable, such as structural scaffolds and other non-enzymatic molecules, for therapeutic purposes. This review focuses on surveying recent progress in developing E3-guided proteolysis-targeting chimeras (PROTACs) and small-molecule chemical modulators of deubiquitinating enzymes upstream of or on the proteasome.

Keywords: PROTAC; deubiquitinating enzyme; induced proteolysis; small-molecules; ubiquitin-proteasome system; undruggable target.

Fig. 1. Mechanisms of induced protein degradation by PROTACs and DUB inhibitors

(Left) General scheme of ubiquitin-proteasome system. An enzymatic cascade of E1-E2-E3 transfers ubiquitin to Lys residues on the substrate. As a consequence, the polyubiquitinated substrate is recognized by the 26S proteasome and undergoes degradation. (Right) Induced proteolysis by PROTAC and/or DUB inhibitor. PROTAC links E3 and the target protein, enhances E3-mediated ubiquitination, and promotes degradation of the target molecule. By contrast, DUBs acting upstream of the proteasome (violet) or on the proteasome (olive drab) can inhibit degradation through substrate deubiquitination. Therefore, DUB inhibitors may facilitate the proteasomal degradation pathway by antagonizing deubiquitination.