A chemical approach for global protein knockdown from mice to non-human primates
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Although conventional genetic modification approaches for protein knockdown work very successfully due to the increasing use of CRISPR/Cas9, effective techniques for achieving protein depletion in adult animals, especially in large animals such as non-human primates, are lacking. Here, we report a chemical approach based on PROTACs technology that efficiently and quickly knocks down FKBP12 (12-kDa FK506-binding) protein globally in vivo. Both intraperitoneal and oral administration led to rapid, robust, and reversible FKBP12 degradation in mice. The efficiency and practicality of this method were successfully demonstrated in both large and small animals (mice, rats, Bama pigs, and rhesus monkeys). Furthermore, we showed this approach can also be applied to effectively knockdown other target proteins such as Bruton's tyrosine kinase (BTK). This chemical protein knockdown strategy provides a powerful research tool for gene function studies in animals, particularly in large animals, for which gene-targeted knockout strategies may remain unfeasible.
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Preclinical and clinical studies have demonstrated multiple routes of administration of PROTACs/IMiDs, including oral.
“Preclinical and clinical studies have demonstrated multiple routes of administration, including oral 18 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [18]
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Natural product-based PROteolysis TArgeting Chimeras (PROTACs)
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Cardiac regeneration: Options for repairing the injured heart
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Self-citationRecent Advances in Optically Controlled PROTAC
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Recent Progress on Microtubule Degradation Agents
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PROTAC: a revolutionary technology propelling small molecule drugs into the next golden age
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Targeting micro-environmental pathways by PROTACs as a therapeutic strategy
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The Role of Protein Engineering in Biomedical Applications of Mammalian Synthetic Biology
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Development of Human Carbonic Anhydrase II Heterobifunctional Degraders
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Development of Degraders of Cyclin-Dependent Kinases 4 and 6 Based on Rational Drug Design
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Chimera induced protein degradation: PROTACs and beyond
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Advancing target validation with PROTAC technology
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Harnessing the Power of Natural Products for Targeted Protein Degradation
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Photocontrolled trimethoprim PROTACs targeting the eDHFR protein tag
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Selective degradation of the estrogen receptor in the treatment of cancers
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Context matters: E3 ligase–ligand pairing strategies for optimized PROTAC performance
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Advancing PROTAC therapeutics through chemistry-guided design of smart delivery systems
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- Authors
- Sun, X., Wang, J., Yao, X., Zheng, W., Mao, Y., Lan, T., Wang, L., Sun, Y., Zhang, X., Zhao, Q., Zhao, J., Xiao, R.-P., Zhang, X., Ji, G., & Rao, Y.
- Affiliations
- Center for Life Sciences (CN)
- Chinese Academy of Sciences (CN)
- Tsinghua University (CN)
- Peking University (CN)
- Corresponding author
- Zhang, Xinyi
- Zhang, Xiuqin
- Ji, Guangju
- Rao, Yu
- ORCID
- Venue
- Cell Discovery
- Published
- 2019-02-05
- Volume
- 5
- Issue
- 1
- Pages
- 10-10
- ISSN
- 2056-5968 (ISSN-L)
- PMC
- PMC6361926
- OpenAlex
- W2914693193
- Cited by
- 118
- References
- 33
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 12 · 2023: 11 · 2022: 12 · 2021: 21 · 2020: 30 · 2019: 11
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Discovery (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81573327)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- PROTACs, Bruton's tyrosine kinase, non-human primates, rhesus monkeys, Bama pig, oral administration, intraperitoneal administration, large animal model, gene function analysis
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