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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.4c01322 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) Degraders for Treating Inflammatory Diseases: Advances and Prospects.
J Med Chem
January 2025
School of Pharmacy, Hangzhou Medical College, Hangzhou 310014, China.
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.
View Article and Find Full Text PDFInterspecies transcriptome profiles of human T cell activation and liver inflammation in a xenogeneic graft-versus-host disease model.
Heliyon
December 2024
Department of Advanced Toxicology Research, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
Background: Xenogeneic transplantation induces acute graft-versus-host disease (aGvHD) and subsequent vital organ damage. Herein, we aimed to examine hepatic damage associated with aGvHD using histopathology and gene expression profiles.
Methods: A xenografic GvHD model was established by engrafting human peripheral blood mononuclear cells (PBMCs) into immunodeficient NOD-scid IL2Rγnull (NSG) mice after busulfan conditioning.
Novel Inhibitory Actions of Neuroactive Steroid [3α,5α]-3-Hydroxypregnan-20-One on Toll-like Receptor 4-Dependent Neuroimmune Signaling.
Biomolecules
November 2024
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Bldg., CB 7178, Chapel Hill, NC 27599, USA.
The endogenous neurosteroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) modulates inflammatory and neuroinflammatory signaling through toll-like receptors (TLRs) in human and mouse macrophages, human blood cells and alcohol-preferring (P) rat brains. Although it is recognized that 3α,5α-THP inhibits TLR4 activation by blocking interactions with MD2 and MyD88, the comprehensive molecular mechanisms remain to be elucidated. This study explores additional TLR4 activation sites, including TIRAP binding to MyD88, which is pivotal for MyD88 myddosome formation, as well as LPS interactions with the TLR4:MD2 complex.
View Article and Find Full Text PDFSmall molecule inhibitors of IL-1R1/IL-1β interaction identified via transfer machine learning QSAR modelling.
Int J Biol Macromol
December 2024
Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; S&K Therapeutics, Ajou University Campus Plaza 418, 199 Worldcup-ro, Yeongtong-gu, Suwon 16502, Republic of Korea. Electronic address:
The human interleukin-1 receptor I (IL-1R1) is a cytokine receptor recognized by interleukin 1β (IL-1β), among other cytokines. Over activation of IL-1R1 has been implicated in various inflammatory conditions. This research aims to identify small-molecule inhibitors targeting the hIL1R1/IL1β interaction, employing a multi-task transfer learning approach for quantitative structure-activity relationship (QSAR) modelling.
View Article and Find Full Text PDFInterleukin-1 Receptor-Associated Kinase 1 in Cancer Metastasis and Therapeutic Resistance: Mechanistic Insights and Translational Advances.
Cells
October 2024
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Interleukin-1 Receptor Associated Kinase 1 (IRAK1) is a serine/threonine kinase that plays a critical role as a signaling transducer of the activated Toll-like receptor (TLR)/Interleukin-1 receptor (IL-1R) signaling pathway in both immune cells and cancer cells. Upon hyperphosphorylation by IRAK4, IRAK1 forms a complex with TRAF6, which results in the eventual activation of the NF-κB and MAPK pathways. IRAK1 can translocate to the nucleus where it phosphorylates STAT3 transcription factor, leading to enhanced IL-10 gene expression.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!