Targeting IRAK4 for Degradation with PROTACs

Nunes, Joao; McGonagle, Grant A.; Eden, Jessica; Kiritharan, Girieshanie; Touzet, Megane; Lewell, Xiao; Emery, John; Eidam, Hilary; Harling, John D.; Anderson, Niall A.

doi:10.1021/acsmedchemlett.9b00219

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

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 +2 more·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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Moving towards more rigid linkers can lead to improved potency and selectivity.
“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]
IRAK4's scaffolding role may only be addressable by PROTAC degraders.
“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]
VHL-based PROTAC degrades IRAK4 in peripheral blood mononuclear cells and dermal fibroblasts with DC50 values of 151 nM and 36 nM, respectively.
“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]
An IRAK4 PROTAC has been shown to be more therapeutically relevant compared to IRAK4 inhibitors in part by removing the scaffolding signaling mediated by IRAK4.
“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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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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › 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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