| Structural highlights
Disease
IRAK4_HUMAN Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:610799. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD.[1] Defects in IRAK4 are the cause of IRAK4 deficiency (IRAK4D) [MIM:607676. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children.[2] [3]
Function
IRAK4_HUMAN Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.[4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
IRAK4 inhibitors are of high interest as treatment for not only inflammatory and autoimmune diseases, but also in the field of oncology. Despite extensive research in the IRAK4 area and progression of several inhibitors into clinical trials, no IRAK4 inhibitor has yet reached the market. In this article, we describe the development of a highly potent and selective IRAK4 lead compound 5e, starting from Astellas AS2444697 (1a). The work includes identification of the pyrazole-pyridine substituent in compound 1g, binding towards the gatekeeper region of IRAK4, followed by a structure-guided scaffold hybridization that led to 5a. Subsequent optimization of substituents of the indazole scaffold yielded 5e, which exhibits a 10-fold improvement in IRAK4 cell potency and higher off-target selectivity compared to AS244697 (1a).
Generation of a potent & selective series of IRAK4 inhibitors based on a structure based, hybridization approach.,Terstiege I, Aagaard A, Berggren K, Bird J, Cumming IA, Groombridge SD, Hidestal L, Johannesson P, Korsgren P, Leuchowius KJ, Lundqvist S, Scott JS, Xue Y, Degorce SL Bioorg Med Chem. 2025 Jul 28;131:118333. doi: 10.1016/j.bmc.2025.118333. PMID:40972347[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ku CL, Picard C, Erdos M, Jeurissen A, Bustamante J, Puel A, von Bernuth H, Filipe-Santos O, Chang HH, Lawrence T, Raes M, Marodi L, Bossuyt X, Casanova JL. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet. 2007 Jan;44(1):16-23. Epub 2006 Sep 1. PMID:16950813 doi:jmg.2006.044446
- ↑ Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med. 2003 Aug 18;198(4):521-31. PMID:12925671 doi:http://dx.doi.org/10.1084/jem.20030701
- ↑ Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A, Casanova JL. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003 Mar 28;299(5615):2076-9. Epub 2003 Mar 13. PMID:12637671 doi:10.1126/science.1081902
- ↑ Li S, Strelow A, Fontana EJ, Wesche H. IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5567-72. PMID:11960013 doi:10.1073/pnas.082100399
- ↑ Burns K, Janssens S, Brissoni B, Olivos N, Beyaert R, Tschopp J. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med. 2003 Jan 20;197(2):263-8. PMID:12538665
- ↑ Qin J, Jiang Z, Qian Y, Casanova JL, Li X. IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness. J Biol Chem. 2004 Jun 18;279(25):26748-53. Epub 2004 Apr 14. PMID:15084582 doi:10.1074/jbc.M400785200
- ↑ Pacquelet S, Johnson JL, Ellis BA, Brzezinska AA, Lane WS, Munafo DB, Catz SD. Cross-talk between IRAK-4 and the NADPH oxidase. Biochem J. 2007 May 1;403(3):451-61. PMID:17217339 doi:10.1042/BJ20061184
- ↑ Koziczak-Holbro M, Joyce C, Gluck A, Kinzel B, Muller M, Tschopp C, Mathison JC, Davis CN, Gram H. IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and toll-like receptor 7-mediated signaling and gene expression. J Biol Chem. 2007 May 4;282(18):13552-60. Epub 2007 Mar 2. PMID:17337443 doi:10.1074/jbc.M700548200
- ↑ Ordureau A, Smith H, Windheim M, Peggie M, Carrick E, Morrice N, Cohen P. The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1. Biochem J. 2008 Jan 1;409(1):43-52. PMID:17997719 doi:10.1042/BJ20071365
- ↑ Dunne A, Carpenter S, Brikos C, Gray P, Strelow A, Wesche H, Morrice N, O'Neill LA. IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). J Biol Chem. 2010 Jun 11;285(24):18276-82. doi: 10.1074/jbc.M109.098137. Epub, 2010 Apr 16. PMID:20400509 doi:10.1074/jbc.M109.098137
- ↑ Terstiege I, Aagaard A, Berggren K, Bird J, Cumming IA, Groombridge SD, Hidestål L, Johannesson P, Korsgren P, Leuchowius KJ, Lundqvist S, Scott JS, Xue Y, Degorce SL. Generation of a potent & selective series of IRAK4 inhibitors based on a structure based, hybridization approach. Bioorg Med Chem. 2025 Jul 28;131:118333. PMID:40972347 doi:10.1016/j.bmc.2025.118333
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