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Targeting IRAK4 for Degradation with PROTACs
Open accessAbstract
Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a key mediator of innate immunity. IRAK4 overactivation is linked with several autoimmune diseases. To date, many IRAK4 inhibitors have been developed to block the protein’s kinase activity with the most advanced reaching Phase II clinical trials. Nevertheless, several reports suggest kinase activity is not disease-relevant in certain cell types, so removing scaffolding signaling in addition to IRAK4 kinase activity may offer a better therapeutic outcome. Herein, we describe the design and synthesis of an IRAK4 Proteolysis Targeted Chimera (PROTAC). We show that IRAK4 degradation induced by compound 9 leads to the inhibition of multiple cytokines in PBMCs. However, in IL-1β stimulated human dermal fibroblasts, inhibition of IL-6 and TNF-α release was not observed despite IRAK4 degradation. Nonetheless, the possibility of targeting both IRAK4 kinase and scaffolding function could potentially lead to new therapeutic opportunities to treat autoimmune, inflammatory, and oncological diseases.
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“Capitalizing on the suggestion that moving towards more rigid linkers can lead to improved potency and selectivity (as exemplified by a recent example using a spirocyclic pyrimidine 68), this structure-based method is also well-positioned to suggest inflexible replacements for the typical PEG and alkyl linkers used in early-stage studies.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [68]
In the citing paper
“and may only be addressable by PROTAC degraders, many of which have been described to date173–175.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [174]
In the citing paper
“Nunes et al. reported a VHL-based PROTAC that was capable of degrading IRAK4 in peripheral blood mononuclear cells and dermal fibroblasts with DC50 values of 151 nM and 36 nM, respectively [184].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [184]
In the citing paper
“an interleukin-1 receptor-associated kinase 4 (IRAK4) PROTAC has been shown to be more therapeutically relevant compared to IRAK4 inhibitors in part by removing the scaffolding signaling mediated by IRAK4 [52].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [52]
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Citations
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HETEROBIFUNCTIONAL DEGRADERS OF IRAK4 FOR AUTOIMMUNE INDICATIONS
Weiss, M. M. (2024) · Medicinal chemistry reviews · doi:10.1021/mc-2024-vol59.ch06
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PROTACs in Action: Bridging Chemical Biology and Drug Discovery for Protein Degradation
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BindingDB Entry 50012690: Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs.
BindingDB (2022) · UC San Diego · doi:10.7270/q2g73jdh
BindingDB Entry 50019825: Developments of PROTACs technology in immune-related diseases.
BindingDB (2024) · UC San Diego · doi:10.7270/q2cr5zrz
BindingDB (2023) · UC San Diego · doi:10.7270/q2vm4h9b
BindingDB (2024) · UC San Diego · doi:10.7270/q2vh5t9d
Metadata
- Authors
- Nunes, J., McGonagle, G. A., Eden, J., Kiritharan, G., Touzet, M., Lewell, X., Emery, J., Eidam, H., Harling, J. D., & Anderson, N. A.
- Affiliations
- GlaxoSmithKline (United Kingdom) (GB)
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Anderson, Niall A.
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-06-14
- Volume
- 10
- Issue
- 7
- Pages
- 1081-1085
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC6627720
- OpenAlex
- W2949458744
- Cited by
- 134
- References
- 17
- Citations by year
- 2026: 5 · 2025: 23 · 2024: 22 · 2023: 21 · 2022: 26 · 2021: 13 · 2020: 20 · 2019: 3
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Keywords
- IRAK4, PROTACs, protein degradation, innate immunity, autoimmune disease, IL-1β, cytokine inhibition, interleukin-6, TNF-α, kinase inhibitors, dermal fibroblasts, peripheral blood mononuclear cells
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