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Recent Developments in PROTAC-Mediated Protein Degradation: From Bench to Clinic
Zhenyi Hu1, Craig M Crews1,2,3
1Department of Molecular, Cellular and Developmental Biology, Yale University, 260 Whitney Avenue, New Haven, CT 06511, USA.
Chembiochem : a European Journal of Chemical Biology
|September 8, 2021
Summary
Proteolysis-targeting chimeras (PROTACs) harness the cell's natural protein disposal system for targeted degradation. Recent advancements focus on mechanisms, pharmacokinetics, and overcoming resistance for therapeutic applications.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis-targeting chimeras (PROTACs) are an innovative therapeutic modality.
- PROTACs leverage the ubiquitin-proteasome system for targeted protein degradation.
- They induce proximity between E3 ligases and target proteins, leading to degradation.
Purpose of the Study:
- To review recent developments in PROTAC technology.
- To highlight advancements in mechanistic and kinetic studies.
- To discuss applications and challenges in PROTAC-mediated protein degradation.
Main Methods:
- Focus on mechanistic and kinetic studies of PROTAC action.
- Examination of pharmacokinetic properties and spatiotemporal control.
- Investigation of covalent PROTACs and resistance mechanisms.
Main Results:
- PROTACs demonstrate therapeutic potential against disease-causing proteins like androgen receptor and BRD4.
- Significant advancements have expanded the range of PROTAC targets.
- Recent developments include novel E3 ligase ligands and strategies to overcome resistance.
Conclusions:
- PROTAC technology has matured significantly over the past two decades.
- Ongoing research addresses key aspects like pharmacokinetics, resistance, and novel E3 ligases.
- PROTACs represent a promising therapeutic strategy with expanding applications.
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