Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2
Open accessAbstract
Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.
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Incorporating a ligand into a PROTAC allows the POI to be degraded without requiring a large excess of drug, resulting in more complete target blockade and a wider therapeutic window.
“By incorporating the ligand into a PROTAC, which often acts in an iterative or ‘pseudo-catalytic’ fashion by binding and facilitating the interaction of its ligase and POI targets, the POI can be degraded without requiring a large excess of drug, thereby resulting in more complete target blockade and a wider therapeutic window22,48.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [48]
PROTACs targeting TRIM24, RIPK2, and JAK family enzymes may have potential to treat certain types of hematologic malignancies but require further studies.
“In addition, PROTACs targeting tripartite motif-containing protein 24 (TRIM24), receptor-interacting protein kinase 2 (RIPK2), and the Janus kinase family enzymes for degradation may also have the potential to be used to treat certain types of hematologic malignancies but require further studies [185–187].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [186]
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References 43 · Cited by 232
- Authors
- Mares, A., Miah, A. H., Smith, I. E. D., Rackham, M., Thawani, A. R., Cryan, J., Haile, P. A., Votta, B. J., Beal, A. M., Capriotti, C., Reilly, M. A., Fisher, D. T., Zinn, N., Bantscheff, M., MacDonald, T. T., Vossenkamper, A., Dace, P., Churcher, I., Benowitz, A. B., Watt, G., Denyer, J., Scott-Stevens, P., & Harling, J. D.
- Affiliations
- GlaxoSmithKline (United Kingdom) (GB)
- GlaxoSmithKline (United States) (US)
- GlaxoSmithKline (Germany) (DE)
- Queen Mary University of London (GB)
- Corresponding author
- Harling, John D.
- ORCID
- Venue
- Communications Biology
- Published
- 2020-03-20
- Volume
- 3
- Issue
- 1
- Pages
- 140-140
- ISSN
- 2399-3642 (ISSN-L)
- PMC
- PMC7083851
- OpenAlex
- W3012324425
- Cited by
- 232
- References
- 43
- Citations by year
- 2026: 31 · 2025: 29 · 2024: 46 · 2023: 38 · 2022: 38 · 2021: 31 · 2020: 19
- FWCI
- 11.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Communications Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- 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 › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, RIPK2, proteasomal degradation, pharmacodynamic response, E3 ubiquitin ligase, low-dose dosing
- MeSH terms
- THP-1 Cells, Animals, Anti-Inflammatory Agents, Colitis, Ulcerative, Crohn Disease, Dose-Response Relationship, Drug, Enzyme Stability, Female, Humans, Inflammation, Injections, Intravenous, Leukocytes, Mononuclear, Male, Drug Design, Cytokines, Rats, Sprague-Dawley, Rats, Wistar, Inflammation Mediators, Ubiquitin-Protein Ligases, Tissue Culture Techniques, Proteasome Endopeptidase Complex, Receptor-Interacting Protein Serine-Threonine Kinase 2, Ubiquitination, Proteolysis
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