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Bioessays. 2018 Apr;40(4):e1700247. doi: 10.1002/bies.201700247. Epub 2018 Feb 23.

PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery.

Gu S1,2, Cui D1,2, Chen X1,2, Xiong X1,2, Zhao Y1,2.

Author information

1
Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, 310003 Hangzhou, China.
2
Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

Abstract

Proteolysis-targeting chimeric molecules (PROTACs) represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate "undruggable" protein targets, such as transcription factors and non-enzymatic proteins, which are not limited to physiological substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery.

KEYWORDS:

E3 ubiquitin ligase; PROTAC; heterobifunctional molecule; protein degradation; proteolysis-targeting chimeric molecule; therapeutic application; undruggable protein target

PMID:
29473971
DOI:
10.1002/bies.201700247
[Indexed for MEDLINE]

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