Cited by 377Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

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Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

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An, Sainan, Fu, Liwu·2018·EBioMedicine

DOI 10.1016/j.ebiom.2018.09.005PMC PMC6197674

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Abstract

There are several challenges towards the development and clinical use of small molecule inhibitors, which are currently the main type of targeted therapies towards intracellular proteins. PROteolysis-TArgeting Chimeras (PROTACs) exploit the intracellular ubiquitin-proteasome system to selectively degrade target proteins. Recently, small-molecule PROTACs with high potency have been frequently reported. In this review, we summarize the emerging characteristics of small-molecule PROTACs, such as inducing a rapid, profound and sustained degradation, inducing a robust inhibition of downstream signals, displaying enhanced target selectivity, and overcoming resistance to small molecule inhibitors. In tumor xenografts, small-molecule PROTACs can significantly attenuate tumor progression. In addition, we also introduce recent developments of the PROTAC technology such as homo-PROTACs. The outstanding advantages over traditional small-molecule drugs and the promising preclinical data suggest that small-molecule PROTAC technology has the potential to greatly promote the development of targeted therapy drugs.

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Authors: An, S., & Fu, L.
Affiliations: Sun Yat-sen University Cancer Center (CN)
Sun Yat-sen University (CN)
Corresponding author: Fu, Liwu
ORCID: Fu, Liwu
Venue: EBioMedicine
Publisher: Elsevier BV
Published: 2018-10
Volume: 36
Pages: 553-562
ISSN: 2352-3964 (ISSN-L)
DOI: 10.1016/j.ebiom.2018.09.005
PMC: PMC6197674
OpenAlex: W2890850288
Cited by: 363
References: 75
Citations by year: 2026: 36 · 2025: 40 · 2024: 57 · 2023: 37 · 2022: 57 · 2021: 55 · 2020: 46 · 2019: 35
FWCI: 3.43
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: EBioMedicine (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders: Natural Science Foundation of Guangdong Province (2016A030312014)
National Key Scientific Instrument and Equipment Development Projects of China (2018ZX09711002-003-011)
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
Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords: PROTACs, targeted protein degradation, ubiquitin-proteasome system, target selectivity, drug resistance, tumor xenografts, intracellular protein degradation, targeted therapy
MeSH terms: Animals, Antineoplastic Agents, Humans, Signal Transduction, Biomarkers, Proteasome Endopeptidase Complex, Small Molecule Libraries, Ubiquitination, Drug Discovery, Molecular Targeted Therapy, Proteolysis, Proteasome Inhibitors

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Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

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