IRAK3

gene
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Also known as IRAK-M

Summary

IRAK3 (interleukin 1 receptor associated kinase 3, HGNC:17020) is a protein-coding gene on chromosome 12q14.3, encoding Interleukin-1 receptor-associated kinase 3 (Q9Y616). Putative inactive protein kinase which regulates signaling downstream of immune receptors including IL1R and Toll-like receptors.

This gene encodes a member of the interleukin-1 receptor-associated kinase protein family. Members of this family are essential components of the Toll/IL-R immune signal transduction pathways. This protein is primarily expressed in monocytes and macrophages and functions as a negative regulator of Toll-like receptor signaling. Mutations in this gene are associated with a susceptibility to asthma. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 11213 — RefSeq curated summary.

At a glance

  • Gene–disease (curated): asthma-related traits, susceptibility to, 5 (Limited, GenCC)
  • GWAS associations: 3
  • Clinical variants (ClinVar): 129 total — 2 likely-pathogenic
  • Druggable target: yes — 35 molecules with ChEMBL bioactivity
  • MANE Select transcript: NM_007199

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:17020
Approved symbolIRAK3
Nameinterleukin 1 receptor associated kinase 3
Location12q14.3
Locus typegene with protein product
StatusApproved
AliasesIRAK-M
Ensembl geneENSG00000090376
Ensembl biotypeprotein_coding
OMIM604459
Entrez11213

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000261233, ENST00000457197, ENST00000545837, ENST00000854785, ENST00000854786, ENST00000947373, ENST00000947374

RefSeq mRNA: 2 — MANE Select: NM_007199 NM_001142523, NM_007199

CCDS: CCDS44937, CCDS8975

Canonical transcript exons

ENST00000261233 — 12 exons

ExonStartEnd
ENSE000008718206620371166203893
ENSE000008718216620945666209520
ENSE000008718226621014766210201
ENSE000008718256621144666211597
ENSE000008718276621717166217235
ENSE000008718296622672366226837
ENSE000008718306622825266228370
ENSE000008718326624448666244684
ENSE000008718336624494866245010
ENSE000008718346624509866245262
ENSE000008718356624769566254622
ENSE000022375516618921466189432

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 94.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.1391 / max 2573.3421, expressed in 1183 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter IDTPM avgSamples expressed
12654416.68551182
1265460.8425104
1265450.448981
1265470.095428
1265480.066920

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
monocyteCL:000057694.76gold quality
mononuclear cellCL:000084294.17gold quality
leukocyteCL:000073893.74gold quality
bone marrowUBERON:000237190.98gold quality
parietal pleuraUBERON:000240090.75gold quality
bloodUBERON:000017890.14gold quality
right lungUBERON:000216789.84gold quality
bone marrow cellCL:000209289.68gold quality
bone elementUBERON:000147489.05gold quality
palpebral conjunctivaUBERON:000181288.42gold quality
pleuraUBERON:000097788.05gold quality
spleenUBERON:000210687.89gold quality
lower lobe of lungUBERON:000894987.81gold quality
trabecular bone tissueUBERON:000248387.16gold quality
calcaneal tendonUBERON:000370186.66gold quality
omental fat padUBERON:001041486.55gold quality
peritoneumUBERON:000235886.45gold quality
adipose tissue of abdominal regionUBERON:000780886.37gold quality
upper lobe of lungUBERON:000894885.39gold quality
upper lobe of left lungUBERON:000895285.37gold quality
granulocyteCL:000009485.27gold quality
visceral pleuraUBERON:000240184.76gold quality
subcutaneous adipose tissueUBERON:000219084.21gold quality
lungUBERON:000204884.06gold quality
adipose tissueUBERON:000101383.88gold quality
connective tissueUBERON:000238483.62gold quality
epithelium of nasopharynxUBERON:000195182.91gold quality
left uterine tubeUBERON:000130382.07gold quality
descending thoracic aortaUBERON:000234581.94gold quality
pericardiumUBERON:000240781.40gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

ExperimentMarker?Max mean expression
E-CURD-119yes25.52
E-ANND-3yes21.25
E-CURD-11no101.69

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3, JUN, NR3C1, STAT3

miRNA regulators (miRDB)

210 targeting IRAK3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-3163100.0077.238605
HSA-MIR-450A-1-3P100.0069.331837
HSA-MIR-3646100.0073.565283
HSA-MIR-3613-3P100.0076.367965
HSA-MIR-432-3P100.0067.86705
HSA-MIR-6740-5P100.0065.64932
HSA-MIR-4713-3P100.0065.92505
HSA-MIR-3134100.0066.43777
HSA-MIR-5011-5P100.0083.465820
HSA-MIR-340-5P100.0072.504437
HSA-MIR-6873-3P100.0071.422626
HSA-MIR-371B-5P99.9975.344759
HSA-MIR-548C-3P99.9974.017587
HSA-MIR-453499.9966.581907
HSA-MIR-366299.9973.825684
HSA-MIR-607799.9968.042299
HSA-MIR-449A99.9971.051776
HSA-MIR-520D-5P99.9873.344883
HSA-MIR-524-5P99.9873.434882
HSA-MIR-477599.9875.006394
HSA-MIR-373-5P99.9875.364753
HSA-MIR-616-5P99.9875.584775
HSA-MIR-1213699.9872.815713
HSA-MIR-569699.9872.364487
HSA-MIR-60799.9773.625593
HSA-MIR-302C-5P99.9772.563642
HSA-MIR-3065-5P99.9771.563281
HSA-MIR-314899.9775.066478
HSA-MIR-1250-3P99.9670.044038
HSA-MIR-3605-5P99.9667.12932

Literature-anchored findings (GeneRIF, showing 40)

  • Identification and characterization of murine IRAK-M (PMID:12054681)
  • Thus, our data indicate that IRAK-M could play a pivotal role in the process of endotoxin tolerance in human monocytes and provide evidence that PI3K is involved in regulating its expression. (PMID:14592437)
  • IRAK-M is rapidly upregulated in human monocytes pre-exposed to tumor cells and could be involved in deactivation of tumor-infiltrating monocytes mediated by tumor cells. (PMID:15728517)
  • These findings indicate that IRAK-M selectively attenuates p38 activation and inhibits innate immunity through stabilizing MKP-1. (PMID:17379480)
  • IRAK-M is involved in the pathogenesis of early-onset persistent asthma. (PMID:17503328)
  • no evidence to suggest association between inflammatory bowel disease, Crohn’s disease (CD), ulcerative colitis (UC) or subsets of CD & UC and IRAK-M; an interaction was found between IRAK-M and CARD15 in UC patients (PMID:17558906)
  • LPS tolerance in human endotoxemia models is associated with IRAK-M up-regulation. (PMID:17982103)
  • Porphyromonas gingivalis lipopolysaccharide upregulates IRAK-M in macrophages. (PMID:18156187)
  • observed striking up-regulation of IRAK-M in monocytes, but without concomitant proinflammatory cytokine production (PMID:18354163)
  • Analysis of single single nucleotide polymorphisms and haplotypes did not reveal a significant association between polymorphisms in the IRAK-M gene and atopic dermatitis in this cohort. (PMID:19013233)
  • Immunosuppression in sepsis caused by B. pseudomallei is associated with an upregulation of IRAK-M and an indicator of poor outcome. (PMID:19114913)
  • IRAK-M is a major mediator of globular adiponectin-induced endotoxin tolerance in primary macrophages (PMID:19414798)
  • Nine SNPs distributed across eight genetic regions (ALOX5, IRAK3, ITGB2, NCF2, NFKB1, SELP, SOD1, and STAT1) were associated with risk of glioma with P value of <0.01. (PMID:19423540)
  • inhibition of LPS-induced NFKB and ERK activation by acute alcohol leads to hyporesponsiveness of monocytes to LPS due to increased IRAK-M; chronic alcohol sensitizes monocytes to LPS through decreased IRAK-M expression and activation of NFKB and ERK (PMID:19561104)
  • Intact IRAK-M is strongly expressed in resting human alveolar macrophages but is cleaved in patients with pneumonia via neutrophil-mediated induction of caspase-6 (CASP-6) activity. (PMID:21098228)
  • Data demonstrates that TGF-beta-dependent induction of IRAK-M expression is an important, clinically relevant mechanism by which tumors may circumvent anti-tumor responses of macrophages. (PMID:21278795)
  • Common SNPs in the IRAK3 gene may be determinants of sepsis-induced acute lung injury. (PMID:21297081)
  • The upregulation of IRAK-M in macrophages is involved in the local immunosuppression around implants, and may contribute to septic and aseptic implant loosening. (PMID:21987497)
  • The results confirm the importance of the IRAK3 in asthma pathogenesis in the European populations (PMID:22070913)
  • these data indicate that epithelial IRAK-M overexpression in T(H)2 cytokine-exposed airways inhibits TLR2 signaling, providing a novel mechanism for the increased susceptibility of infections in asthmatic patients. (PMID:22154382)
  • Data suggest further evaluation of IRAK3 as a diagnostic and prognostic marker, and as a target for intervention. (PMID:22272346)
  • the tested variations of IRAK-M and SIGIRR genes do not confer a relevant role in the susceptibility to systemic lupus erythematosus in European-descent populations (PMID:22634523)
  • these data identify an important signaling regulator in human macrophages that is used by surfactant to control the long-term alveolar inflammatory response, i.e., enhanced IRAK-M activity. (PMID:22886503)
  • IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFjB activation to produce inhibitory molecules (PMID:23376919)
  • our study demonstrates that patients carrying IRAK-M+22148 G haplotype are more susceptible to sepsis than patients carrying IRAK-M+22148 A haplotype, suggesting that IRAK-M+22148 G haplotype might be a risk factor for sepsis. (PMID:23588345)
  • These data indicate the enhancing effect of IRAK-M on epithelial human rhinovirus-16 infection, which is partly through the autophagic pathway. (PMID:24074582)
  • The structure function of the death domain of human IRAK-M (PMID:25481771)
  • IRAK-M expression is upregulated in peripheral blood cells from idiopathic pulmonary fibrosis patients (PMID:25595781)
  • HIF1alpha is a regulator of monocyte functional re-programming in sepsis via regulating IRAKM expression. (PMID:25746953)
  • IRAK3 methylation was associated with tumor stage and poor prognosis of hepatocellular carcinoma patients. (PMID:25852282)
  • Alpha-Melanocyte-Stimulating Hormone Suppresses TLR2-Mediated Functional Responses through IRAK-M in Normal Human Keratinocytes (PMID:26309029)
  • Data indicate a strong positive correlation between interleukin-1 receptor-associated kinase 3 (IRAK-M) and pSTAT3 protein in colorectal cancer (CRC). (PMID:27150039)
  • Rs11541076 in IRAK3, a negative regulator of TLR signalling, as a predictor of anti-TNF treatment response. (PMID:27698401)
  • IRAK-M functions to modulate inflammatory signaling pathways and is critical in maintaining immune system homeostasis in the gut. However, increased IRAK-M is associated with increased disease pathogenesis and increased cancer severity in human patients. (PMID:27939424)
  • MERS-CoV S protein binds to DPP4 to suppress macrophage activation via induction of IRAK-M, PPARgamma and the immunosuppressive cytokine IL-10. (PMID:28118607)
  • Clinical trial with house dust mite allergen challenge of asthmatic patients reveal that IRAK-M is a PIN1 target critical for IL-33 signaling in allergic asthma. NMR analysis and docking simulations suggest that PIN1 might regulate IRAK-M conformation and function in IL-33 signaling. (PMID:29686383)
  • Study determined that the expression of a novel circRNA, circIRAK3, was increased in metastatic breast cancer (BC) cells and predictive of BC recurrence and identified miR-3607 as a circIRAK3-associated miRNA. FOXC1 the target of miR-3607, was downregulated in circIRAK3-silenced cells and mediated circIRAK3-induced BC cell migration. FOXC1 in turn could bind to the IRAK3 promoter, triggering a positive-feedback loop. (PMID:29803789)
  • TLR stimulation led to IRAKM-caspase-8-ASC complex formation, resulting in the activation of caspase-8 and IL-1beta release in microglia. (PMID:30372424)
  • Findings demonstrated a distinctive role of IRAK-M in maintaining chronic Th2 airway inflammation and indicated a complex role for IRAK-M in the initiation and progression of experimental allergic asthma. (PMID:30617222)
  • IRAK3 modulates downstream innate immune signalling through its guanylate cyclase activity. (PMID:31664109)

Cross-species orthologs

9 orthologs

OrganismSymbolGene ID
danio_rerioirak3ENSDARG00000053131
mus_musculusIrak3ENSMUSG00000020227
rattus_norvegicusIrak3ENSRNOG00000004226
drosophila_melanogasterpllFBGN0010441
drosophila_melanogasterHaspinFBGN0046706
caenorhabditis_elegansWBGENE00004029
caenorhabditis_eleganshasp-1WBGENE00007258
caenorhabditis_elegansWBGENE00012159
caenorhabditis_eleganshasp-2WBGENE00021214

Paralogs (4): IRAK2 (ENSG00000134070), HASPIN (ENSG00000177602), IRAK1 (ENSG00000184216), IRAK4 (ENSG00000198001)

Protein

Protein identifiers

Interleukin-1 receptor-associated kinase 3Q9Y616 (reviewed: Q9Y616)

Alternative names: IL-1 receptor-associated kinase M, Inactive IL-1 receptor-associated kinase 3

All UniProt accessions (2): Q9Y616, F5GYN6

UniProt curated annotations — full annotation on UniProt →

Function. Putative inactive protein kinase which regulates signaling downstream of immune receptors including IL1R and Toll-like receptors. Inhibits dissociation of IRAK1 and IRAK4 from the Toll-like receptor signaling complex by either inhibiting the phosphorylation of IRAK1 and IRAK4 or stabilizing the receptor complex. Upon IL33-induced lung inflammation, positively regulates expression of IL6, CSF3, CXCL2 and CCL5 mRNAs in dendritic cells.

Subunit / interactions. Monomer. Homodimer; disulfide-linked. May interact with IRAK4 (when phosphorylated). Interacts (when phosphorylated at Ser-110) with PIN1 (via WW domain) in response to IL33-mediated (but not TLR4 ligand LPS) dendritic cell stimulation.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in eosinophils, dendritic cells and/or monocytes (at protein level). Expressed predominantly in peripheral blood lymphocytes.

Disease relevance. Asthma-related traits 5 (ASRT5) [MIM:611064] Asthma-related traits include clinical symptoms of asthma, such as coughing, wheezing, dyspnea, bronchial hyperresponsiveness as assessed by methacholine challenge test, serum IgE levels, atopy and atopic dermatitis. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Domain organisation. The nucleotide binding domain binds ATP with low affinity.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.

Isoforms (2)

UniProt IDNamesCanonical?
Q9Y616-11yes
Q9Y616-22

RefSeq proteins (2): NP_001135995, NP_009130* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR000488Death_domDomain
IPR000719Prot_kinase_domDomain
IPR011009Kinase-like_dom_sfHomologous_superfamily
IPR011029DEATH-like_dom_sfHomologous_superfamily
IPR042698IRAK3_PKDomain
IPR042747IRAK3_deathDomain

Pfam: PF00069, PF00531

UniProt features (73 total): helix 22, sequence variant 15, strand 14, mutagenesis site 5, binding site 4, domain 2, modified residue 2, disulfide bond 2, turn 2, chain 1, splice variant 1, region of interest 1, sequence conflict 1, site 1

Structure

Experimental structures (PDB)

3 structures.

PDBMethodResolution (Å)
6ZIWX-RAY DIFFRACTION2.18
6RUUX-RAY DIFFRACTION2.95
5UKESOLUTION NMR

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q9Y616-F171.790.40

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 110–111 (cis/trans isomerization of proline peptide bond; by pin1; dependent on ser-110 phosphorylation)

Ligand- & substrate-binding residues (4): 171–179; 192; 295–298; 311

Post-translational modifications (2): 467, 110

Disulfide bonds (2): 202, 287

Mutagenesis-validated functional residues (5):

PositionPhenotype
110abolishes phosphorylation. abolishes interaction with pin1. reduces protein stability.
110phosphomimic. slight decrease in the interaction with pin1. weak interaction with pin1 in absence of il33-mediated dendr
210abolishes dimerization.
214enhances dimerization.
467no effect on the interaction with pin1.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

IDPathway
R-HSA-166058MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-9020702Interleukin-1 signaling
R-HSA-1280215Cytokine Signaling in Immune system
R-HSA-166016Toll Like Receptor 4 (TLR4) Cascade
R-HSA-168179Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168188Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249Innate Immune System
R-HSA-168256Immune System
R-HSA-168898Toll-like Receptor Cascades
R-HSA-181438Toll Like Receptor 2 (TLR2) Cascade
R-HSA-446652Interleukin-1 family signaling
R-HSA-449147Signaling by Interleukins

MSigDB gene sets: 305 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_TOLERANCE_INDUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_PRODUCTION_OF_MOLECULAR_MEDIATOR_OF_IMMUNE_RESPONSE, CHUNG_BLISTER_CYTOTOXICITY_DN, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, PID_IL1_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (30): positive regulation of cytokine production (GO:0001819), negative regulation of cytokine-mediated signaling pathway (GO:0001960), MyD88-dependent toll-like receptor signaling pathway (GO:0002755), protein phosphorylation (GO:0006468), Toll signaling pathway (GO:0008063), response to virus (GO:0009615), positive regulation of macrophage tolerance induction (GO:0010933), negative regulation of macrophage cytokine production (GO:0010936), cytokine-mediated signaling pathway (GO:0019221), lipopolysaccharide-mediated signaling pathway (GO:0031663), response to peptidoglycan (GO:0032494), response to lipopolysaccharide (GO:0032496), negative regulation of interleukin-12 production (GO:0032695), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), negative regulation of toll-like receptor signaling pathway (GO:0034122), intracellular signal transduction (GO:0035556), negative regulation of protein catabolic process (GO:0042177), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), negative regulation of protein-containing complex disassembly (GO:0043242), regulation of protein-containing complex disassembly (GO:0043244), response to exogenous dsRNA (GO:0043330), negative regulation of MAPK cascade (GO:0043409), negative regulation of innate immune response (GO:0045824), interleukin-1-mediated signaling pathway (GO:0070498), response to interleukin-1 (GO:0070555), positive regulation of immune system process (GO:0002684), signal transduction (GO:0007165), regulation of innate immune response (GO:0045088)

GO Molecular Function (9): magnesium ion binding (GO:0000287), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein kinase binding (GO:0019901), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-10 pathways:

CategoryPathways
Immune System2
Toll-like Receptor Cascades2
Toll Like Receptor 2 (TLR2) Cascade2
Toll Like Receptor 4 (TLR4) Cascade1
Toll Like Receptor TLR1:TLR2 Cascade1
Toll Like Receptor TLR6:TLR2 Cascade1
Interleukin-1 family signaling1
Innate Immune System1
Signaling by Interleukins1
Cytokine Signaling in Immune system1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cell surface receptor signaling pathway3
negative regulation of signal transduction2
toll-like receptor signaling pathway2
response to molecule of bacterial origin2
response to oxygen-containing compound2
negative regulation of cytokine production2
intracellular anatomical structure2
canonical NF-kappaB signal transduction2
regulation of canonical NF-kappaB signal transduction2
protein dimerization activity2
cytokine production1
regulation of cytokine production1
positive regulation of gene expression1
positive regulation of multicellular organismal process1
regulation of cytokine-mediated signaling pathway1
cytokine-mediated signaling pathway1
negative regulation of response to cytokine stimulus1
phosphorylation1
protein modification process1
response to other organism1
positive regulation of tolerance induction1
macrophage tolerance induction1
regulation of macrophage tolerance induction1
negative regulation of cytokine production involved in immune response1
macrophage cytokine production1
regulation of macrophage cytokine production1
cellular response to cytokine stimulus1
cellular response to lipopolysaccharide1
response to nitrogen compound1
response to lipid1
interleukin-12 production1
regulation of interleukin-12 production1
interleukin-6 production1
regulation of interleukin-6 production1
tumor necrosis factor production1
regulation of tumor necrosis factor production1
negative regulation of tumor necrosis factor superfamily cytokine production1
negative regulation of immune system process1
regulation of toll-like receptor signaling pathway1
signal transduction1

Protein interactions and networks

STRING

2322 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
IRAK3IRAK1P51617984
IRAK3IRAK2O43187974
IRAK3IRAK4Q9NWZ3947
IRAK3MYD88P78397924
IRAK3TRAF6Q9Y4K3863
IRAK3SIGIRRQ6IA17843
IRAK3IL1R1P14778781
IRAK3TLR4O00206774
IRAK3TLR2O60603770
IRAK3INPP5DQ92835736
IRAK3TOLLIPQ9H0E2707
IRAK3TLR5O60602664
IRAK3TLR9Q9NR96660
IRAK3TLR3O15455647
IRAK3TLR8Q9NR97645

IntAct

33 interactions, top by confidence:

ABTypeScore
TRAF6IRAK3psi-mi:“MI:0915”(physical association)0.680
IRAK3TRAF6psi-mi:“MI:0915”(physical association)0.680
IRAK1IRAK3psi-mi:“MI:0915”(physical association)0.560
IRAK2IRAK3psi-mi:“MI:0915”(physical association)0.560
IRAK3IRAK1psi-mi:“MI:0915”(physical association)0.560
IRAK3IRAK2psi-mi:“MI:0915”(physical association)0.560
IRAK3IRAK2psi-mi:“MI:0914”(association)0.560
IRAK3CD14psi-mi:“MI:0915”(physical association)0.440
IRAK3HOXB7psi-mi:“MI:0915”(physical association)0.440
IRAK3CD14psi-mi:“MI:0403”(colocalization)0.440
HOXB7IRAK3psi-mi:“MI:0403”(colocalization)0.440
IRAK3KRT8psi-mi:“MI:0915”(physical association)0.400
IRAK3KRT18psi-mi:“MI:0915”(physical association)0.400
IRAK3MYD88psi-mi:“MI:0915”(physical association)0.400
IRAK3IRAK3psi-mi:“MI:0915”(physical association)0.400
TICAM2IRAK3psi-mi:“MI:0915”(physical association)0.400
HSP90AB1IRAK3psi-mi:“MI:0915”(physical association)0.400
ATP6V0BIRAK3psi-mi:“MI:0915”(physical association)0.370
IRAK3COPB1psi-mi:“MI:0915”(physical association)0.370
IRAK3ECM1psi-mi:“MI:0915”(physical association)0.370
FOLR1IRAK3psi-mi:“MI:0915”(physical association)0.370
IRAK3CDCA5psi-mi:“MI:0915”(physical association)0.370
IRAK3ADH1Bpsi-mi:“MI:0915”(physical association)0.370
NONOIRAK3psi-mi:“MI:0915”(physical association)0.370
NTRK3IRAK3psi-mi:“MI:0915”(physical association)0.370
LDB1IRAK3psi-mi:“MI:0915”(physical association)0.370
NSA2IRAK3psi-mi:“MI:0915”(physical association)0.370
ABL1psi-mi:“MI:0914”(association)0.350
IRAK3H2AZ1psi-mi:“MI:0914”(association)0.350
IRAK3CD44psi-mi:“MI:0914”(association)0.350

BioGRID (35): TRAF6 (Two-hybrid), IRAK3 (Proximity Label-MS), IRAK3 (Proximity Label-MS), IRAK3 (Affinity Capture-Western), IRAK3 (Affinity Capture-Western), RNF152 (Affinity Capture-Western), IRAK3 (Proximity Label-MS), IRAK3 (Affinity Capture-Western), CD44 (Affinity Capture-MS), DPP8 (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), TBK1 (Affinity Capture-MS), HSPB8 (Affinity Capture-MS), H2AFZ (Affinity Capture-MS), HIST2H2AC (Affinity Capture-MS)

ESM2 similar proteins: A4Q9F4, A6QLH5, D3Z7P3, D3ZVU9, E9PV86, M0R7T9, O35652, O43414, O54804, O60242, O60347, O70512, O94925, P08887, P0C7M8, P13264, P35790, P85298, Q01134, Q08DW9, Q13202, Q13505, Q2HJ53, Q2TBM7, Q3UGX3, Q4R766, Q4R7M4, Q58DH2, Q5XI70, Q62225, Q6AYT7, Q6DN14, Q80T74, Q80UW0, Q80ZF8, Q86W50, Q8C460, Q8N2K0, Q8NBA8, Q8NHH1

Diamond homologs: A0A0P0XII1, C0LGD7, C0LGG7, C0LGU1, C0LGU5, D7UPN3, F4JEQ2, F4JPX3, G5ECP4, O22187, O22476, O43187, O48814, O49839, O49840, O65472, O65530, O80719, O80939, P43293, P46573, P51617, P93050, Q05652, Q06548, Q0P5I2, Q0WRY5, Q1PDV6, Q1PDW3, Q1PE89, Q1PEM5, Q1RMT8, Q2LGB3, Q39086, Q3E9X6, Q3EDL4, Q5PP29, Q5R810, Q5WA76, Q5XF79

SIGNOR signaling

3 interactions.

AEffectBMechanism
IRAK3down-regulatesIRAK4binding
NR3C1“up-regulates quantity”IRAK3“transcriptional regulation”
IRAK3“down-regulates activity”Inflammation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

PathwayPartnersFoldFDR
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation654.4×1e-07
MyD88 dependent cascade initiated on endosome654.4×1e-07
Toll Like Receptor 7/8 (TLR7/8) Cascade543.9×4e-06
Toll Like Receptor 9 (TLR9) Cascade541.8×5e-06
MyD88:MAL(TIRAP) cascade initiated on plasma membrane536.2×8e-06
Toll Like Receptor 4 (TLR4) Cascade531.2×1e-05
Toll-like Receptor Cascades529.6×2e-05
Cytokine Signaling in Immune system59.7×1e-03

GO biological processes:

GO termPartnersFoldFDR
toll-like receptor 4 signaling pathway6131.7×2e-09
positive regulation of type I interferon production587.8×4e-07
positive regulation of canonical NF-kappaB signal transduction824.2×2e-07
cellular response to lipopolysaccharide520.4×2e-04
inflammatory response69.4×1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

129 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic0
Likely pathogenic2
Uncertain significance93
Likely benign13
Benign6

Top pathogenic / likely-pathogenic (2)

Variant IDHGVSClassification
423059NM_007199.3(IRAK3):c.1218_1219insTGA (p.Val407Ter)Likely pathogenic
503865NM_007199.3(IRAK3):c.1148dup (p.Arg384fs)Likely pathogenic

SpliceAI

2928 predictions. Top by Δscore:

VariantEffectΔscore
12:66203700:A:AGacceptor_gain1.0000
12:66203701:A:Gacceptor_gain1.0000
12:66210144:TAG:Tacceptor_loss1.0000
12:66210145:A:AGacceptor_gain1.0000
12:66210145:AGG:Aacceptor_loss1.0000
12:66210146:G:GGacceptor_gain1.0000
12:66210198:AAAG:Adonor_loss1.0000
12:66210199:AAGG:Adonor_loss1.0000
12:66210200:AGG:Adonor_loss1.0000
12:66210201:GGTAT:Gdonor_loss1.0000
12:66210202:G:GAdonor_loss1.0000
12:66210203:T:Gdonor_loss1.0000
12:66211444:A:Gacceptor_gain1.0000
12:66217236:G:GGdonor_gain1.0000
12:66245095:AAGC:Aacceptor_gain1.0000
12:66245095:AAGCG:Aacceptor_gain1.0000
12:66189431:GG:Gdonor_gain0.9900
12:66189432:GG:Gdonor_gain0.9900
12:66189432:GGTG:Gdonor_loss0.9900
12:66189433:G:GAdonor_loss0.9900
12:66189434:T:Gdonor_loss0.9900
12:66190115:T:Gdonor_gain0.9900
12:66209491:G:GTdonor_gain0.9900
12:66209492:A:Tdonor_gain0.9900
12:66210142:CTTA:Cacceptor_loss0.9900
12:66210145:AG:Aacceptor_gain0.9900
12:66210146:GG:Gacceptor_gain0.9900
12:66211443:A:AGacceptor_gain0.9900
12:66211443:AAG:Aacceptor_gain0.9900
12:66244550:C:CAacceptor_gain0.9900

AlphaMissense

3948 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
12:66189420:T:AW41R0.996
12:66189420:T:CW41R0.996
12:66203834:T:CL86P0.993
12:66245247:A:CR433S0.990
12:66245247:A:TR433S0.990
12:66189422:G:CW41C0.988
12:66189422:G:TW41C0.988
12:66228273:T:AW264R0.988
12:66228273:T:CW264R0.988
12:66245246:G:CR433T0.988
12:66203806:G:CA77P0.987
12:66189396:G:CD33H0.986
12:66203776:A:CS67R0.986
12:66203778:T:AS67R0.986
12:66203778:T:GS67R0.986
12:66203795:T:CL73P0.986
12:66203846:T:CL90P0.984
12:66228283:G:CR267P0.984
12:66245221:T:CC425R0.983
12:66189417:G:CG40R0.982
12:66203783:C:AT69K0.982
12:66203797:T:AW74R0.980
12:66203797:T:CW74R0.980
12:66244680:G:AG361E0.979
12:66189430:T:CL44P0.978
12:66245245:A:GR433G0.978
12:66244673:A:CS359R0.977
12:66244675:C:AS359R0.977
12:66244675:C:GS359R0.977
12:66211585:A:CK192N0.976

dbSNP variants (sampled 300 via entrez): RS1000027530 (12:66236547 G>A), RS1000177646 (12:66235857 C>T), RS1000209533 (12:66238992 A>T), RS1000245350 (12:66187870 T>C), RS1000333745 (12:66242043 G>A,C,T), RS1000341406 (12:66232063 C>T), RS1000370917 (12:66219183 G>T), RS1000396243 (12:66224993 A>C), RS1000579389 (12:66222905 A>G), RS1000616881 (12:66229781 C>T), RS1000627962 (12:66235541 C>G), RS1000672279 (12:66231725 A>T), RS1000673079 (12:66230388 T>C), RS1000690764 (12:66229178 C>G), RS1000785344 (12:66228688 A>C)

Disease associations

OMIM: gene MIM:604459 | disease phenotypes: MIM:142623, MIM:611064

GenCC curated gene-disease

DiseaseClassificationInheritance
asthma-related traits, susceptibility to, 5LimitedAutosomal dominant

Mondo (2): Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), asthma-related traits, susceptibility to, 5 (MONDO:0012607)

Orphanet (1): Hirschsprung disease (Orphanet:388)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

StudyTraitp-value
GCST002361_26Smooth-surface caries3.000000e-07
GCST005976_21White blood cell count (basophil)2.000000e-10
GCST011398_6Response to esketamine in treatment resistant depression4.000000e-08

EFO canonical traits (2, from GWAS)

EFO IDTrait name
EFO:0005090basophil count
EFO:0009748response to ketamine

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL4742326 (PROTEIN-PROTEIN INTERACTION), CHEMBL4748234 (PROTEIN-PROTEIN INTERACTION), CHEMBL5081 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

35 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 279,917 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

MoleculeNamePhasePatents
CHEMBL1287853FEDRATINIB43,554
CHEMBL2035187PACRITINIB43,345
CHEMBL2103830FOSTAMATINIB43,841
CHEMBL3301622GILTERITINIB42,395
CHEMBL477772PAZOPANIB415,540
CHEMBL502835NINTEDANIB48,545
CHEMBL535SUNITINIB479,020
CHEMBL601719CRIZOTINIB414,403
CHEMBL608533MIDOSTAURIN47,259
CHEMBL939GEFITINIB4117,814
CHEMBL2105728CRENOLANIB32,167
CHEMBL31965CANERTINIB38,083
CHEMBL603469LESTAURTINIB3
CHEMBL1230609FORETINIB23,096
CHEMBL1236962OMIPALISIB23,989
CHEMBL124660TANDUTINIB22,530
CHEMBL1721885SU-0148132363
CHEMBL1822792MK-24612686
CHEMBL1944698ZOTIRACICLIB22,915
CHEMBL215152DEFOSBARASERTIB2372
CHEMBL475251R-4062
CHEMBL521851PICTILISIB2
CHEMBL564829MILCICLIB2
CHEMBL572878TOZASERTIB2
CHEMBL1908394GSK-4613641
CHEMBL1908397KW-24491
CHEMBL1952329SGI-17761
CHEMBL259084MLN-80541
CHEMBL296468BMS-3870321
CHEMBL3544932TAK-9011

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Interleukin-1 receptor-associated kinase (IRAK) family

Most potent curated ligand interactions (1 total), top 1:

LigandActionAffinityParameter
IRAK3 PROTAC 23Binding8.3pIC50

Binding affinities (BindingDB)

12 measured of 12 human assays (12 total across all organisms); most potent 12 below. Values come from heterogeneous assays and are not directly comparable.

LigandMeasureValuePatent
StaurosporineKD1.7 nM
PKC-412KD190 nM
4-[[7-[2,6-bis(fluoranyl)phenyl]-9-chloranyl-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acidKD300 nM
4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamideKD740 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamideKD1100 nM
CI-1033KD1700 nM
BMS-387072KD1800 nM
GEFITINIBIC502300 nMUS-9416123: Kinase modulators for the treatment of cancer
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamideKD2600 nM
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamideKD2900 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3bKD3100 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamideKD3500 nM

ChEMBL bioactivities

106 potent at pChembl≥5 of 107 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
8.40IC504nMCHEMBL4788568
8.40IC504nMCHEMBL4763746
8.30IC505nMCHEMBL4749646
8.22IC506nMCHEMBL4744403
8.22IC506nMCHEMBL4777817
8.22IC506nMCHEMBL4798668
8.15Kd7nMGILTERITINIB
8.00IC5010nMCHEMBL4094760
8.00IC5010nMCHEMBL4779593
7.96Kd11nMR-406
7.95Kd11.24nMCHEMBL5653589
7.92Kd12nMCHEMBL3688339
7.89IC5013nMCHEMBL4791281
7.89Kd13nMSTAUROSPORINE
7.82IC5015nMCHEMBL4754560
7.80Kd16nMLESTAURTINIB
7.72IC5019nMCHEMBL4779139
7.68IC5021nMCHEMBL4762658
7.68IC5021nMCHEMBL4757434
7.68IC5021nMCHEMBL4747690
7.66IC5022nMCHEMBL4746543
7.62Kd24nMMK-5108
7.62IC5024nMCHEMBL4763804
7.60IC5025nMCHEMBL4787051
7.58Kd26nMSGI-1776
7.58ED5026.22nMCHEMBL5653589
7.57Kd27nMTAK-901
7.57IC5027nMCHEMBL4064608
7.51IC5031nMCHEMBL4278882
7.51Kd31nMCRIZOTINIB
7.48IC5033nMCHEMBL4752190
7.48IC5033nMCHEMBL4753038
7.47IC5034nMCHEMBL4743058
7.47Kd34nMCHEMBL4749646
7.46Kd35nMPACRITINIB
7.37Kd43nMR-406
7.30IC5050nMCHEMBL4778668
7.29IC5051nMCHEMBL4750934
7.24Kd57nMCYC-116
7.10Kd80nMXL-228
7.03Kd93nMCHEMBL4064608
6.92Kd120nMFEDRATINIB
6.83Kd147nMLESTAURTINIB
6.80Kd160nMTAE-684
6.75Kd180nMMIDOSTAURIN
6.62Kd240nMKW-2449
6.59Kd254nMK-252A
6.54Kd291nMMILCICLIB
6.54Kd286nMZOTIRACICLIB
6.43Kd370nMFORETINIB

PubChem BioAssay actives

98 with measured affinity, of 538 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
2-(1-methyl-2,6-dioxopiperidin-3-yl)-5-[4-[2-[1-[4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanoyl]piperidin-4-yl]ethyl]piperazin-1-yl]isoindole-1,3-dione1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0040uM
1-[4-[4-[(5-propan-2-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethanone1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0040uM
2-(2,6-dioxopiperidin-3-yl)-5-[4-[2-[1-[4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanoyl]piperidin-4-yl]ethyl]piperazin-1-yl]isoindole-1,3-dione1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0050uM
1-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethanone1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0060uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[7-[[4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanoyl]amino]heptanoylamino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0060uM
2-(2,6-dioxopiperidin-3-yl)-5-[4-[[1-[4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanoyl]piperidin-4-yl]methyl]piperazin-1-yl]isoindole-1,3-dione1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0060uM
Gilteritinib1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.0070uM
N-(4-morpholin-4-ylcyclohexyl)-5-(oxan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0100uM
N-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethyl]-4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0100uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one625066: Binding constant for IRAK3 kinase domainkd0.0110uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2148602: Binding affinity to human IRAK3 incubated for 45 mins by Kinobead based pull down assaykd0.0112uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.0120uM
N-[4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]butyl]-4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0130uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one435528: Binding constant for IRAK3 kinase domainkd0.0130uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[4-[[4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanoyl]amino]butanoylamino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0150uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one507570: Binding affinity to IRAK3kd0.0160uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-[2-[[4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0190uM
N-[6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]hexyl]-4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0210uM
N-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]-4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0210uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-[2-oxo-2-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0210uM
N-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0220uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[[4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0240uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-[[4-oxo-4-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]butanoyl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0250uM
N-[(1-methylpiperidin-4-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]imidazo[1,2-b]pyridazin-6-amine1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.0260uM
5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.0270uM
Crizotinib625066: Binding constant for IRAK3 kinase domainkd0.0310uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-[2-[2-[2-oxo-2-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0330uM
2-(2,6-dioxopiperidin-3-yl)-4-[2-[2-[2-[2-[2-[3-oxo-3-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]isoindole-1,3-dione1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0330uM
2-(2,6-dioxopiperidin-3-yl)-4-[2-[2-[2-[3-oxo-3-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]propoxy]ethoxy]ethoxy]ethylamino]isoindole-1,3-dione1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0340uM
Pacritinib1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.0350uM
2-(2,6-dioxopiperidin-3-yl)-4-[2-[2-[2-[2-[3-oxo-3-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]propoxy]ethoxy]ethoxy]ethoxy]ethylamino]isoindole-1,3-dione1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0500uM
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-[2-[2-oxo-2-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide1723774: Inhibition of kinase tracer 236 binding to recombinant human full-length GST-tagged IRAK3 expressed in insect cells by Lanthascreen Eu kinase binding assayic500.0510uM
4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.0570uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-N-[(3-propan-2-yl-1,2-oxazol-5-yl)methyl]pyrimidine-2,4-diamine1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.0800uM
Fedratinib625066: Binding constant for IRAK3 kinase domainkd0.1200uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine625066: Binding constant for IRAK3 kinase domainkd0.1600uM
Midostaurin435528: Binding constant for IRAK3 kinase domainkd0.1800uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone625066: Binding constant for IRAK3 kinase domainkd0.2400uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-16-carboxylate1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.2540uM
(16E)-14-methyl-20-oxa-5,7,14,27-tetrazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2(27),3,5,8,10,12(26),16,21,23-decaene1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.2860uM
N,1,4,4-tetramethyl-8-[4-(4-methylpiperazin-1-yl)anilino]-5H-pyrazolo[4,5-h]quinazoline-3-carboxamide1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.2910uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide625066: Binding constant for IRAK3 kinase domainkd0.3700uM
N-methyl-6-(trifluoromethyl)-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine1673297: Binding affinity to human wild type partial length IRAK3 (V147 to E596 residues) expressed in bacterial expression system by Kinomescan methodkd0.4800uM
14-[[[(2R)-1,4-dioxan-2-yl]methyl-methylsulfamoyl]amino]-5-(1-methylpyrazol-4-yl)-2-oxo-7-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaene1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.5020uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2148602: Binding affinity to human IRAK3 incubated for 45 mins by Kinobead based pull down assaykd0.5768uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one625066: Binding constant for IRAK3 kinase domainkd0.6100uM
4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide435528: Binding constant for IRAK3 kinase domainkd0.7300uM
N-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-6-[(6-fluoropyrazolo[1,5-a]pyrimidin-5-yl)amino]-4-(propan-2-ylamino)pyridine-3-carboxamide1664785: Inhibition of human wild type partial length IRAK3 (147 to 596 residues) expressed in bacterial expression systemic500.7600uM
4-(2-methyl-3-propan-2-ylimidazol-4-yl)-N-(4-methylsulfonylphenyl)pyrimidin-2-amine1425028: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.7710uM
Pazopanib435528: Binding constant for IRAK3 kinase domainkd0.8000uM

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
sodium arseniteincreases expression2
Vehicle Emissionsdecreases expression, decreases reaction, increases expression2
Lipopolysaccharidesincreases expression2
aristolochic acid Idecreases expression1
trichostatin Aincreases expression1
potassium chromate(VI)affects cotreatment, decreases expression1
epigallocatechin gallateaffects cotreatment, decreases expression1
di-n-butylphosphoric acidaffects expression1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amidedecreases expression, decreases reaction1
incobotulinumtoxinAincreases expression1
(+)-JQ1 compounddecreases expression1
Norethindrone Acetateaffects cotreatment, increases expression1
Acetaminophendecreases expression1
Air Pollutantsdecreases expression, increases abundance1
Allergensincreases expression1
Benzo(a)pyreneincreases methylation1
Diethylhexyl Phthalatedecreases expression1
Doxorubicindecreases expression1
Estradiolaffects cotreatment, increases expression1
Formaldehydedecreases expression1
Hyaluronic Acidincreases expression1
Methyl Methanesulfonatedecreases expression1
Progesteroneincreases expression1
Silicon Dioxideincreases methylation1
Smokedecreases expression, increases abundance1
Tetradecanoylphorbol Acetateaffects cotreatment, affects expression1
Tobacco Smoke Pollutionincreases expression1
Valproic Acidincreases expression1
Vanadatesdecreases expression1
Zincaffects cotreatment, affects expression1

ChEMBL screening assays

147 unique, capped per target: 147 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL4729440BindingProtac activity at CRBN/IRAK3 in LPS-induced human THP1 cells assessed as induction of IRAK3 degradation at 1 uM by Western blot analysis relative to controlDiscovery of Proteolysis-Targeting Chimera Molecules that Selectively Degrade the IRAK3 Pseudokinase. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

CellosaurusNameCategorySex
CVCL_B9YEAbcam THP-1 IRAK3 KOCancer cell lineMale
CVCL_E0FAUbigene HeLa IRAK3 KOCancer cell lineFemale
CVCL_SS86HAP1 IRAK3 (-)Cancer cell lineMale

Clinical trials (associated diseases)

48 trials via MONDO — disease-level, not drug-specific.

TrialPhaseStatusTitle
NCT02343562PHASE4UNKNOWNProbiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647PHASE4COMPLETEDLaparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT04904081PHASE3UNKNOWNFeasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00630838PHASE2COMPLETEDProbiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT01985646EARLY_PHASE1COMPLETEDA Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712Not specifiedRECRUITINGHirschsprung Disease Genetic Study
NCT01515501Not specifiedCOMPLETEDEndoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168Not specifiedRECRUITINGRare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809Not specifiedUNKNOWNGenetic Mosaicism in Hirschsprung’s Disease
NCT02193685Not specifiedUNKNOWNIdentification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994Not specifiedUNKNOWNA New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008Not specifiedCOMPLETED3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176Not specifiedUNKNOWNEnhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205Not specifiedCOMPLETEDMICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812Not specifiedUNKNOWNLaparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03666767Not specifiedCOMPLETEDManagement and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939Not specifiedCOMPLETEDThe Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947Not specifiedUNKNOWNTransition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093Not specifiedUNKNOWNThe Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120Not specifiedCOMPLETEDeHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976Not specifiedUNKNOWNOstomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225Not specifiedCOMPLETEDInduced Pluripotent Stem Cells for Disease Research
NCT04598841Not specifiedCOMPLETEDNutrition Support for Hirschsprung Disease
NCT04622410Not specifiedRECRUITINGRegistry for Hirschsprung Disease of the BELAPS
NCT04624334Not specifiedTERMINATEDNon-invasive Assessment of Colonic Motility
NCT04730128Not specifiedCOMPLETEDTranslation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients
NCT04837963Not specifiedCOMPLETEDDoes Hirschsprung Disease Increase the Risk of Febrile Urinary Tract Infection in Children
NCT04957667Not specifiedCOMPLETEDScintigraphic Defecography for Evaluation of Functional Outcome in an Adult Hirschsprung Population
NCT05038345Not specifiedTERMINATEDHirschsprung Disease Trends in the United States: Analysis of the National Inpatient Sample
NCT05044741Not specifiedCOMPLETEDRisk Factors of Perforated HSCR in Neonates
NCT05293353Not specifiedUNKNOWNNeokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05307419Not specifiedUNKNOWNFull Thickness vs. Rectal Suction Biopsy in the Diagnosis of Hirschsprungs Disease
NCT05450991Not specifiedRECRUITINGLong-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05655845Not specifiedUNKNOWNRisk Factors for Bowel Dysfunction at Preschool and Early Childhood Age in Children With Hirschsprung Disease
NCT06072976Not specifiedRECRUITINGThe Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies
NCT06197061Not specifiedUNKNOWNComparison of Robot-assisted With Laparoscopic-assisted Modified Soave Procedure for Classical Hirschsprung Disease
NCT06573723Not specifiedRECRUITINGInstitutional Registry of Rare Diseases
NCT06590142Not specifiedRECRUITINGHirschsprung’s Advances; Working Towards Autologous tIssue therapIes
NCT06592534Not specifiedNOT_YET_RECRUITINGBabies With Enterocolitis - A Study of Faecal Calprotectin in Hirschsprung Disease (The BEACH Study)
NCT06650683Not specifiedRECRUITINGImpact of Providing Nursing Support on Parental Stress Related to Preoperative Care of a Newborn with Hirschsprung’s Disease