2. Academic Validation
  3. Recent Developments in PROTAC-Mediated Protein Degradation: From Bench to Clinic

Recent Developments in PROTAC-Mediated Protein Degradation: From Bench to Clinic

  • Chembiochem. 2022 Jan 19;23(2):e202100270. doi: 10.1002/cbic.202100270.
Zhenyi Hu 1,  Craig M Crews 1 2 3
Affiliations

Affiliations

  • 1 Department of Molecular, Cellular and Developmental Biology, Yale University, 260 Whitney Avenue, New Haven, CT 06511, USA.
  • 2 Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06511, USA.
  • 3 Department of Pharmacology, Yale University, 333 Cedar Street, New Haven, CT 06511, USA.
PMID: 34494353 DOI: 10.1002/cbic.202100270
Abstract

Proteolysis-targeting chimeras (PROTACs), an emerging paradigm-shifting technology, hijacks the ubiquitin-proteasome system for targeted protein degradation. PROTACs induce ternary complexes between an E3 Ligase and POI, and this induced proximity leads to polyUb chain formation on substrates and eventual proteasomal-mediated POI degradation. PROTACs have shown great therapeutic potential by degrading many disease-causing proteins, such as the Androgen Receptor and BRD4. The PROTAC technology has advanced significantly in the last two decades, with the repertoire of PROTAC targets increased tremendously. Herein, we describe recent developments of PROTAC technology, focusing on mechanistic and kinetic studies, pharmacokinetic study, spatiotemporal control of PROTACs, covalent PROTACs, resistance to PROTACs, and new E3 ligands.

Keywords

E3; PROTAC; mechanistic and kinetic studies; pharmacokinetic; resistance.

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