Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) Degraders for Treating Inflammatory Diseases: Advances and Prospects

  • J Med Chem. 2025 Jan 23;68(2):902-914. doi: 10.1021/acs.jmedchem.4c01322.
Yaoxiang Lin  1  2 ,  Lulu Zheng  3 ,  Ying Xu  1 ,  Xinyan Wang  4 ,  Jie Li  4 ,  Lei Zheng  1 ,  Guang Liang  1 ,  Lingfeng Chen  1
Affiliations
  • 1. School of Pharmacy, Hangzhou Medical College, Hangzhou 310014, China.
  • 2. School of Medicine, Hangzhou Normal University, Hangzhou 311121, China.
  • 3. Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou 310000, China.
  • 4. School of Medicine, Zhejiang University City College, Huzhou Road, Hangzhou 310015, China.
PMID: 39762193 DOI: 10.1021/acs.jmedchem.4c01322
Abstract

Interleukin-1 receptor-associated kinase 4 (IRAK4) is involved in various inflammation-related diseases. Both the kinase and scaffolding functions of IRAK4 initiate pro-inflammatory factor transcription and expression. The scaffolding function of IRAK4 is essential for Myddosome assembly and NF-κB activation. Conventional small-molecule inhibitors effectively inhibit the kinase function of IRAK4 but do not block its scaffolding function. Recently, various IRAK4 degraders have shown promising therapeutic potential in inflammatory diseases. The most advanced IRAK4-selective degrader, KT-474 (SAR444656), significantly reduced inflammatory biomarker levels in patients and demonstrated high safety and tolerability. This perspective introduces and discusses the physiological biology of IRAK4, its associated diseases, and the current development of IRAK4 degraders, thereby offering insights into future research directions.

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