interleukin 1 receptor associated kinase 4 | Interleukin-1 receptor-associated kinase (IRAK) family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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interleukin 1 receptor associated kinase 4

Target id: 2045

Nomenclature: interleukin 1 receptor associated kinase 4

Abbreviated Name: IRAK4

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

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: ON :     interleukin 1 receptor associated kinase 4 has curated data in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 460 12q12 IRAK4 interleukin 1 receptor associated kinase 4
Mouse - 459 15 F1 Irak4 interleukin-1 receptor-associated kinase 4
Rat - 461 7 q35 Irak4 interleukin-1 receptor-associated kinase 4
Previous and Unofficial Names
Renal carcinoma antigen NY-REN-64 | interleukin-1 receptor-associated kinase 4
Database Links
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
RefSeq Nucleotide
RefSeq Protein
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of IRAK-4
Resolution:  2.0Å
Species:  Human
References:  24
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of IRAK4 kinase domain complexed with AMP-PNP
Ligand:  AMP-PNP
Resolution:  2.3Å
Species:  Human
References:  15
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of IRAK4 in complex with compound 30 (PF-06650833)
Ligand:  PF-06650833
Resolution:  2.02Å
Species:  Human
References:  16
Enzyme Reaction
EC Number:

Download all structure-activity data for this target as a CSV file

Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
ND-2158 Hs Inhibition 9.0 pKi 7
pKi 9.0 (Ki 1x10-9 M) [7]
ND-2110 Hs Inhibition 8.1 pKi 7
pKi 8.1 (Ki 7.5x10-9 M) [7]
PF-06650833 Hs Inhibition 9.7 pIC50 16
pIC50 9.7 (IC50 2x10-10 M) [16]
PF-06426779 Hs Inhibition 9.5 pIC50 2
pIC50 9.5 (IC50 3x10-10 M) [2]
IRAK4 inhibitor rac-45 [PMID: 18501603] Hs Inhibition 9.0 pIC50 4
pIC50 9.0 (IC50 1x10-9 M) [4]
compound 1 [WO2012007375] Hs Inhibition 9.0 pIC50 3
pIC50 9.0 (IC50 1x10-9 M) [3]
compound 7 [WO2012007375] Hs Inhibition 8.1 pIC50 3
pIC50 8.1 (IC50 8x10-9 M) [3]
IRAK4 inhibitor 4b [PMID: 18474425] Hs Inhibition 7.7 pIC50 5
pIC50 7.7 (IC50 2x10-8 M) [5]
Takinib Hs Inhibition 6.9 pIC50 23
pIC50 6.9 (IC50 1.2x10-7 M) [23]
IRAK-1/4 inhibitor Hs Inhibition 6.7 pIC50 21
pIC50 6.7 (IC50 2x10-7 M) [21]
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
Reference: 10,25

Key to terms and symbols Click column headers to sort
Target used in screen: IRAK4
Ligand Sp. Type Action Affinity Units
staurosporine Hs Inhibitor Inhibition 8.8 pKd
lestaurtinib Hs Inhibitor Inhibition 8.8 pKd
sunitinib Hs Inhibitor Inhibition 7.2 pKd
vandetanib Hs Inhibitor Inhibition 7.1 pKd
NVP-TAE684 Hs Inhibitor Inhibition 7.1 pKd
SU-14813 Hs Inhibitor Inhibition 7.1 pKd
dovitinib Hs Inhibitor Inhibition 6.9 pKd
tamatinib Hs Inhibitor Inhibition 6.8 pKd
bosutinib Hs Inhibitor Inhibition 6.4 pKd
gefitinib 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
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.

Reference: 1,13

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 Hs Inhibitor Inhibition 1.0 -2.0 0.0
Syk inhibitor Hs Inhibitor Inhibition 3.0 0.0 -1.0
staurosporine Hs Inhibitor Inhibition 3.5 1.0 0.5
JAK3 inhibitor VI Hs Inhibitor Inhibition 8.3 3.0 1.0
SB 218078 Hs Inhibitor Inhibition 14.0 38.0 18.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 19.6 8.0 0.0
SU11652 Hs Inhibitor Inhibition 22.7 22.0 7.0
IRAK-1/4 inhibitor Hs Inhibitor Inhibition 22.8 13.0 15.0
sunitinib Hs Inhibitor Inhibition 27.4
dovitinib Hs Inhibitor Inhibition 31.8
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
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


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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. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

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

20. 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]

21. 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]

22. 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]

23. 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]

24. 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]

25. 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 12/03/2018. Accessed on 20/01/2019. IUPHAR/BPS Guide to PHARMACOLOGY,