Cited by 137Protein Degradation and InhibitorsChemical Synthesis and AnalysisMonoclonal and Polyclonal Antibodies Research

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Targeting IRAK4 for Degradation with PROTACs

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Nunes, Joao, McGonagle, Grant A., Eden, Jessica, Kiritharan, Girieshanie, Touzet, Megane, Lewell, Xiao, Emery, John, Eidam, Hilary, Harling, John D., Anderson, Niall A.·2019·ACS Medicinal Chemistry Letters

DOI 10.1021/acsmedchemlett.9b00219PMC PMC6627720

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Abstract

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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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.
ORCID: Eden, Jessica
Eidam, Hilary
Harling, John D.
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)
DOI: 10.1021/acsmedchemlett.9b00219
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: doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-045 (stm-asf)
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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Targeting IRAK4 for Degradation with PROTACs

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