Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs
Open accessAbstract
Interleukin-1 receptor associated kinase 4 (IRAK4) is a promising therapeutic target for diffuse large B-cell lymphoma driven by MYD88 L265P mutant, acting both as a kinase and a scaffolding protein for downstream signaling molecules. While previous efforts to modulate IRAK4 activity with kinase inhibitors alone displayed moderate efficacy, protein degradation may offer a solution to blocking both IRAK4 kinase activity and scaffolding capabilities. To this end, the potent IRAK4 degrader 9 was discovered, and it effectively inhibited the activation of downstream NF-κB signaling and outperformed the parent compound 1 . In addition, compound 9 displayed a substantial advantage in reduction of the viability of OCI-LY10 and TMD8 cells over the parent compound 1 . These results underline the potential that eliminating both the kinase and scaffolding functions of IRAK4 may result in superior and broader efficacy than inhibiting the kinase activity alone.
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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 [175]
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Cites
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PROTAC targeted protein degraders: the past is prologue
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- Authors
- Chen, Y., Ning, Y., Bai, G., Tong, L., Zhang, T., Zhou, J., Zhang, H., Xie, H., Ding, J., & Duan, W.
- Affiliations
- China Pharmaceutical University (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Zhang, Huibin
- Xie, Hua
- Ding, Jian
- Duan, Wenhu
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-12-10
- Volume
- 12
- Issue
- 1
- Pages
- 82-87
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC7812674
- OpenAlex
- W3112568052
- Cited by
- 49
- References
- 23
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 12 · 2023: 10 · 2022: 9 · 2021: 2
- FWCI
- 1.70
- 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)
- Funders
- Ministry of Science and Technology of the People's Republic of China (2018ZX09711002-011-016)
- Science and Technology Commission of Shanghai Municipality (18431907100)
- National Natural Science Foundation of China (21702220)
- Chinese Academy of Sciences (XDA12020228)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- IRAK4, PROTACs, diffuse large B-cell lymphoma, MYD88 L265P, protein degradation, kinase inhibitors, scaffold proteins, NF-κB signaling, small molecule synthesis
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