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

Gu, Shanshan; Cui, Danrui; Chen, Xiaoyu; Xiong, Xiufang; Zhao, Yongchao

doi:10.1002/bies.201700247

Cited by 239Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

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

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Gu, Shanshan, Cui, Danrui, Chen, Xiaoyu, Xiong, Xiufang, Zhao, Yongchao·2018·BioEssays

DOI 10.1002/bies.201700247

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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.

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Within this complex, the target protein is tagged with ubiquitin, facilitating its recognition and subsequent degradation by the proteasome.
“Within this complex, the target protein is tagged with ubiquitin, facilitating its recognition and subsequent degradation by the proteasome.480,481”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [480]
As a heterobifunctional molecule, PROTAC simultaneously targets the protein of interest and the E3 ubiquitin ligase, forming a ternary complex.
“As a heterobifunctional molecule, PROTAC simultaneously targets the protein of interest and the E3 ubiquitin ligase, forming a ternary complex.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [480]
At the core of PROTAC's mechanism of action lies the degradation of target proteins via the ubiquitin-proteasome system (UPS).
“At the core of PROTAC’s mechanism of action lies the degradation of target proteins via the ubiquitin-proteasome system (UPS).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [480]

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Authors: Gu, S., Cui, D., Chen, X., Xiong, X., & Zhao, Y.
Affiliations: First Affiliated Hospital Zhejiang University (CN)
Corresponding author: Xiong, Xiufang
Zhao, Yongchao
ORCID: Gu, Shanshan
Cui, Danrui
Chen, Xiaoyu
Xiong, Xiufang
Zhao, Yongchao
Venue: BioEssays
Publisher: Wiley
Published: 2018-02-23
Volume: 40
Issue: 4
Pages: e1700247-e1700247
ISSN: 0265-9247 (ISSN-L)
1521-1878
DOI: 10.1002/bies.201700247
OpenAlex: W2792290561
Cited by: 231
References: 69
Citations by year: 2026: 14 · 2025: 34 · 2024: 29 · 2023: 22 · 2022: 33 · 2021: 31 · 2020: 30 · 2019: 30 · 2018: 8
FWCI: 2.45
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: BioEssays (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Natural Science Foundation of Zhejiang Province (LR16C050001)
National Natural Science Foundation of China (31470753, 31501129, 81572708, 81672728)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Keywords: PROTACs, protein degradation, E3 ubiquitin ligase, heterobifunctional molecules, ubiquitin-proteasome system, drug discovery, linker design, tissue distribution, drug stability
MeSH terms: Animals, Humans, Proteins, Transcription Factors, Ubiquitin-Protein Ligases, Drug Discovery, Proteolysis

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

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