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interleukin 1 receptor associated kinase 4

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 2045

Nomenclature: interleukin 1 receptor associated kinase 4

Abbreviated Name: IRAK4

Family: Interleukin-1 receptor-associated kinase (IRAK) family

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 460 12q12 IRAK4 interleukin 1 receptor associated kinase 4
Mouse - 459 15 E3 Irak4 interleukin-1 receptor-associated kinase 4
Rat - 461 7q35 Irak4 interleukin-1 receptor-associated kinase 4
Previous and Unofficial Names Click here for help
Renal carcinoma antigen NY-REN-64 | interleukin-1 receptor-associated kinase 4
Database Links Click here for help
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of IRAK-4
PDB Id:  2NRU
Resolution:  2.0Å
Species:  Human
References:  26
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of IRAK4 kinase domain complexed with AMP-PNP
PDB Id:  2OID
Ligand:  AMP-PNP
Resolution:  2.3Å
Species:  Human
References:  17
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of IRAK4 in complex with compound 30 (PF-06650833)
PDB Id:  5UIU
Ligand:  PF-06650833
Resolution:  2.02Å
Species:  Human
References:  18
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of IRAK4 kinase in complex with the inhibitor CA-4948
PDB Id:  7C2V
Ligand:  emavusertib
Resolution:  2.44Å
Species:  Human
References:  15
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
ND-2158 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 9.0 pKi 8
pKi 9.0 (Ki 1x10-9 M) [8]
ND-2110 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.1 pKi 8
pKi 8.1 (Ki 7.5x10-9 M) [8]
PF-06650833 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 9.7 pIC50 18
pIC50 9.7 (IC50 2x10-10 M) [18]
PF-06426779 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 9.5 pIC50 2
pIC50 9.5 (IC50 3x10-10 M) [2]
IRAK4 inhibitor rac-45 [PMID: 18501603] Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 9.0 pIC50 5
pIC50 9.0 (IC50 1x10-9 M) [5]
compound 1 [WO2012007375] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.0 pIC50 3
pIC50 9.0 (IC50 1x10-9 M) [3]
compound 7 [WO2012007375] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 3
pIC50 8.1 (IC50 8x10-9 M) [3]
zabedosertib Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 4
pIC50 8.0 (IC50 1.07x10-8 M) [4]
IRAK4 inhibitor 4b [PMID: 18474425] Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.7 pIC50 6
pIC50 7.7 (IC50 2x10-8 M) [6]
emavusertib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 15
pIC50 7.5 (IC50 3.17x10-8 M) [15]
Takinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.9 pIC50 25
pIC50 6.9 (IC50 1.2x10-7 M) [25]
IRAK-1/4 inhibitor Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.7 pIC50 23
pIC50 6.7 (IC50 2x10-7 M) [23]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 11,27

Key to terms and symbols Click column headers to sort
Target used in screen: IRAK4
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.8 pKd
lestaurtinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 8.8 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 7.1 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 6.9 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.8 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.4 pKd
gefitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 1,14

Key to terms and symbols Click column headers to sort
Target used in screen: IRAK4/IRAK4
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Small molecule or natural product Hs Inhibitor Inhibition 1.0 -2.0 0.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 3.0 0.0 -1.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.5 1.0 0.5
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 8.3 3.0 1.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 14.0 38.0 18.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 19.6 8.0 0.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 22.7 22.0 7.0
IRAK-1/4 inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 22.8 13.0 15.0
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 27.4
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 31.8
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
IRAK4 is essential for most innate immune responses to bacteria and viruses, and IRAK4 deficiency (caused by mutations) has been shown to result in recurrent invasive pneumococcal disease [20].

The mechanistic explanation for IRAK4's importance is revealed in this proteins central role in TLR/IL-1R superfamily signalling (this superfamily of proteins includes the Toll-like receptors and receptors for pro-inflammatory cytokines IL-1 and IL-18, which all share a Toll/IL-1R homology (TIR) domain in their intracellular region). Signalling via TIR-containing receptors depends on the formation of a multi-protein complex termed the Myddosome, so-named as hierarchical complex formation begins with recruitment of the TIR-containing adaptor protein MyD88 [22]. MyD88 recruits IRAK4 and this complex further recruits the IRAK4 substrates IRAK2 or the related IRAK1 [19]. Formation of the Myddosome brings the IRAK kinase domains in to proximity, facilitating phosphorylation and activation and ultimately activation of transcription factors NF-κB, AP-1 and IRFs (e.g. IRF5 [10]) to stimulate anti-pathogen responses and inflammation [13,21].

The development of clinically useful IRAK4 inhibitors is underway, with investigational indications including autoimmune and inflammatory diseases, and cancer. Lead compounds in development pipelines include BMS-986126, ND-346 and CA-4948 which are being considered as therapuetics for SLE, lymphomas and other malignancies [12,16]. However, any preclinical assessment should address the relevance of IRAK4 splice variants which may influence inhibitor selectivity and/or expression profile, as well as considering the side effects of inhibiting such a crucial enzyme. Other areas for potential development include: Cardiac inflammation and damage (TLR4 activation in response to ischaemia), CNS and neuropathic pain (TLR4 receptors are upregulated in neuropathic pain and in neuroinflammatory states, particularly on microglia) [7], asthma [9], multiple sclerosis and other Th17-driven immunological conditions [24].

As an alternative to IRAK4 inhibition, Kymera Therapeutics have developed an orally delivered IRAK4 selective ubiquitin-mediated protein degrader molecule (KT-474) that they are initially progressing for atopic dermatitis and hidradenitis suppurativa (see NCT04772885). KT-474 is designed to block IRAK4-mediated inflammatory signalling in two independent ways; 1) inhibiting IRAK4 kinase activity and, 2) disrupting its scaffold function in myddosome assembly. KT-474 offers clinical potential beyond dermatologic indications, such as in rheumatic, respiratory and gastrointestinal inflammatory diseases. KT-474 is the first molecular degrader class drug to enter clinical development for non-oncology indications.
Immuno Process Associations
Immuno Process:  Inflammation
Comment:  IRAK4 is involved in Myddosome formation which regulates transcription factor activation and drives cytokine production to effect anti-pathogen responses and inflammation [13,21].
GO Annotations:  Associated to 2 GO processes
GO:0045087 innate immune response TAS
GO:1990266 neutrophil migration IMP
Immuno Process:  Immune regulation
Comment:  IRAK4 is involved in Myddosome formation which regulates transcription factor activation and drives cytokine production to effect anti-pathogen responses and inflammation [13,21].
Immuno Process:  Cytokine production & signalling
Comment:  IRAK4 is involved in Myddosome formation which regulates transcription factor activation and drives cytokine production to effect anti-pathogen responses and inflammation [13,21].
GO Annotations:  Associated to 3 GO processes
GO:0019221 cytokine-mediated signaling pathway IBA
GO:0070498 interleukin-1-mediated signaling pathway IBA
click arrow to show/hide IEA associations
GO:0001816 cytokine production IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:1990266 neutrophil migration IMP
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Invasive pneumococcal disease, recurrent isolated, 1; IPD1
OMIM: 610799
Disease:  IRAK4 deficiency
Synonyms: Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency [Orphanet: ORPHA70592]
OMIM: 607676
Orphanet: ORPHA70592

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Anderson DR, Bunnage ME, Curran KJ, Dehnhardt CM, Gavrin LK, Goldberg JA, Han S, Hepworth D, Huang H-C, Lee A et al.. (2015) Bicyclic-fused heteroaryl or aryl compounds and their use as IRAK4 inhibitors. Patent number: WO2015150995. Assignee: Pfizer Inc.. Priority date: 04/04/2014. Publication date: 08/10/2015.

3. Arora N, Chen S, Hermann JC, KuglstatterA, Labadie SS, Lin CJJ, Lucas MC, Moore AG, Papp E, Talamas FX et al.. (2012) Pyrazolo [1, 5a] pyrimidine and thieno [3, 2b] pyrimidine derivatives as irak4 modulators. Patent number: WO2012007375. Assignee: F. Hoffmann-La Roche Ag. Priority date: 13/11/2015. Publication date: 19/01/2012.

4. Bothe U, Siebenreicher H, Schmidt N, Nubbemeyer R,Bomer U, Gunther J, Steuber H, Lange M, Stegmann C, Sutter A, Rausch A. (2016) New substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said new substituted indazoles, and use of said new substituted indazoles to produce drugs. Patent number: WO2016083433A1. Assignee: Bayer Pharma. Priority date: 26/11/2014. Publication date: 02/02/2016.

5. Buckley GM, Fosbeary R, Fraser JL, Gowers L, Higueruelo AP, James LA, Jenkins K, Mack SR, Morgan T, Parry DM et al.. (2008) IRAK-4 inhibitors. Part III: a series of imidazo[1,2-a]pyridines. Bioorg Med Chem Lett, 18 (12): 3656-60. [PMID:18501603]

6. Buckley GM, Gowers L, Higueruelo AP, Jenkins K, Mack SR, Morgan T, Parry DM, Pitt WR, Rausch O, Richard MD et al.. (2008) IRAK-4 inhibitors. Part 1: a series of amides. Bioorg Med Chem Lett, 18 (11): 3211-4. [PMID:18474425]

7. Caso JR, Pradillo JM, Hurtado O, Leza JC, Moro MA, Lizasoain I. (2008) Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and in the worsening of experimental stroke. Stroke, 39 (4): 1314-20. [PMID:18309167]

8. Chaudhary D, Robinson S, Romero DL. (2015) Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders. J Med Chem, 58 (1): 96-110. [PMID:25479567]

9. Chun E, Lee SH, Lee SY, Shim EJ, Cho SH, Min KU, Kim YY, Park HW. (2010) Toll-like receptor expression on peripheral blood mononuclear cells in asthmatics; implications for asthma management. J Clin Immunol, 30 (3): 459-64. [PMID:20072849]

10. Cushing L, Winkler A, Jelinsky SA, Lee K, Korver W, Hawtin R, Rao VR, Fleming M, Lin LL. (2017) IRAK4 kinase activity controls Toll-like receptor-induced inflammation through the transcription factor IRF5 in primary human monocytes. J Biol Chem, 292 (45): 18689-18698. [PMID:28924041]

11. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

12. Dudhgaonkar S, Ranade S, Nagar J, Subramani S, Prasad DS, Karunanithi P, Srivastava R, Venkatesh K, Selvam S, Krishnamurthy P et al.. (2017) Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity. J Immunol, 198 (3): 1308-1319. [PMID:28003376]

13. Dunne A, O'Neill LA. (2003) The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci STKE, 2003 (171): re3. [PMID:12606705]

14. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

15. Gummadi VR, Boruah A, Ainan BR, Vare BR, Manda S, Gondle HP, Kumar SN, Mukherjee S, Gore ST, Krishnamurthy NR et al.. (2020) Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies. ACS Med Chem Lett, 11 (12): 2374-2381. [PMID:33335659]

16. Kelly PN, Romero DL, Yang Y, Shaffer 3rd AL, Chaudhary D, Robinson S, Miao W, Rui L, Westlin WF, Kapeller R et al.. (2015) Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy. J Exp Med, 212 (13): 2189-201. [PMID:26621451]

17. Kuglstatter A, Villaseñor AG, Shaw D, Lee SW, Tsing S, Niu L, Song KW, Barnett JW, Browner MF. (2007) Cutting Edge: IL-1 receptor-associated kinase 4 structures reveal novel features and multiple conformations. J Immunol, 178 (5): 2641-5. [PMID:17312103]

18. Lee KL, Ambler CM, Anderson DR, Boscoe BP, Bree AG, Brodfuehrer JI, Chang JS, Choi C, Chung S, Curran KJ et al.. (2017) Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. J Med Chem, 60 (13): 5521-5542. [PMID:28498658]

19. Lin SC, Lo YC, Wu H. (2010) Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature, 465 (7300): 885-90. [PMID:20485341]

20. Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN. (2003) Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med, 198 (4): 521-31. [PMID:12925671]

21. Narayanan KB, Park HH. (2015) Toll/interleukin-1 receptor (TIR) domain-mediated cellular signaling pathways. Apoptosis, 20 (2): 196-209. [PMID:25563856]

22. O'Neill LA, Bowie AG. (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol, 7 (5): 353-64. [PMID:17457343]

23. Powers JP, Li S, Jaen JC, Liu J, Walker NP, Wang Z, Wesche H. (2006) Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4. Bioorg Med Chem Lett, 16 (11): 2842-5. [PMID:16563752]

24. Staschke KA, Dong S, Saha J, Zhao J, Brooks NA, Hepburn DL, Xia J, Gulen MF, Kang Z, Altuntas CZ et al.. (2009) IRAK4 kinase activity is required for Th17 differentiation and Th17-mediated disease. J Immunol, 183 (1): 568-77. [PMID:19542468]

25. Totzke J, Gurbani D, Raphemot R, Hughes PF, Bodoor K, Carlson DA, Loiselle DR, Bera AK, Eibschutz LS, Perkins MM et al.. (2017) Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease. Cell Chem Biol, 24 (8): 1029-1039.e7. [PMID:28820959]

26. Wang Z, Liu J, Sudom A, Ayres M, Li S, Wesche H, Powers JP, Walker NP. (2006) Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper. Structure, 14 (12): 1835-44. [PMID:17161373]

27. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

How to cite this page

Interleukin-1 receptor-associated kinase (IRAK) family: interleukin 1 receptor associated kinase 4. Last modified on 02/03/2021. Accessed on 13/04/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2045.