Details

Autor(en) / Beteiligte

• Li, Ke
• Crews, Craig M

Titel

PROTACs: past, present and future

Ist Teil von

• Chemical Society reviews, 2022-06, Vol.51 (12), p.5214-5236

Ort / Verlag

England: Royal Society of Chemistry

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of one ligand that binds to a protein of interest (POI) and another that can recruit an E3 ubiquitin ligase. The chemically-induced proximity between the POI and E3 ligase results in ubiquitination and subsequent degradation of the POI by the ubiquitin-proteasome system (UPS). The event-driven mechanism of action (MOA) of PROTACs offers several advantages compared to traditional occupancy-driven small molecule inhibitors, such as a catalytic nature, reduced dosing and dosing frequency, a more potent and longer-lasting effect, an added layer of selectivity to reduce potential toxicity, efficacy in the face of drug-resistance mechanisms, targeting nonenzymatic functions, and expanded target space. Here, we highlight important milestones and briefly discuss lessons learned about targeted protein degradation (TPD) in recent years and conjecture on the efforts still needed to expand the toolbox for PROTAC discovery to ultimately provide promising therapeutics. This review highlights important milestones in the evolution of PROTACs, briefly discusses recent lessons about targeted protein degradation, and conjectures on the efforts still needed to expand the toolbox for PROTAC discovery.