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Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs
Open accessAbstract
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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“The small molecule thalidomide, which binds to the ubiquitously expressed E3 ligase substrate adapter Cereblon (CRBN), has often been used as the E3 ligase-binding moiety in degraders[11].”
From Development of dual and selective degraders of cyclin-dependent kinases 4 and 6 (2019) · cites this paper as [11]
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BindingDB (2021) · UC San Diego · doi:10.7270/q23f4t3t
Metadata
- 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)
- 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
- 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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