proteolysistargeting

Proteolysis targeting, commonly called targeted protein degradation, is a therapeutic strategy that aims to remove specific proteins from cells rather than simply inhibit their activity. It leverages the cell’s ubiquitin-proteasome system to mark a chosen protein for destruction. The field encompasses several modalities, most notably proteolysis-targeting chimeras (PROTACs), as well as molecular glues and other degraders that direct proteins to degradative pathways.

In the prototypical PROTAC, a bifunctional molecule contains two ligands joined by a linker: one binds the target protein and the other recruits an E3 ubiquitin ligase. When the PROTAC bridges the two, an E3 ligase ubiquitinates the target, leading to its recognition and destruction by the proteasome. This process can operate catalytically, meaning a single PROTAC molecule can trigger multiple rounds of degradation. Because degradation removes the protein rather than merely inhibiting it, the approach can potentially address proteins previously deemed undruggable.

Variants include molecular glues, which induce a novel interaction between an E3 ligase and the target without a linker, and lysosome- or autophagy-based degraders such as LYTACs, AUTACs, and ATTEC. Advantages include the possibility of substoichiometric activity and overcoming resistance to inhibition. Challenges include achieving precise selectivity, managing pharmacokinetic properties, and preventing off-target ubiquitination or compensatory pathways. Resistance can arise from mutations in the target or the recruited E3 ligase.

In research and drug discovery, proteolysis targeting is an active area with several degrader candidates advancing through preclinical and clinical development. Notable examples from industry include PROTACs that target the androgen receptor and estrogen receptor, among others, developed by companies such as Arvinas. The field continues to evolve as new ligases, targets, and degraders are explored.