IRAK4

Summary

IRAK4 (interleukin 1 receptor associated kinase 4, HGNC:17967) is a protein-coding gene on chromosome 12q12, encoding Interleukin-1 receptor-associated kinase 4 (Q9NWZ3). Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens.

This gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. The protein is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 51135 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 67 (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 387 total — 30 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes — 43 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_016123

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17967
Approved symbol	IRAK4
Name	interleukin 1 receptor associated kinase 4
Location	12q12
Locus type	gene with protein product
Status	Approved
Aliases	NY-REN-64
Ensembl gene	ENSG00000198001
Ensembl biotype	protein_coding
OMIM	606883
Entrez	51135

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 11 nonsense_mediated_decay, 10 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000440781, ENST00000546780, ENST00000547101, ENST00000547521, ENST00000547928, ENST00000550361, ENST00000550386, ENST00000550615, ENST00000550616, ENST00000551736, ENST00000552309, ENST00000613694, ENST00000696790, ENST00000696791, ENST00000696792, ENST00000696794, ENST00000696795, ENST00000696796, ENST00000851160, ENST00000851161, ENST00000851162, ENST00000851163, ENST00000937192, ENST00000955808

RefSeq mRNA: 13 — MANE Select: NM_016123 NM_001114182, NM_001145256, NM_001145257, NM_001145258, NM_001351338, NM_001351339, NM_001351340, NM_001351341, NM_001351342, NM_001351343, NM_001351344, NM_001351345, NM_016123

CCDS: CCDS44862, CCDS8744

Canonical transcript exons

ENST00000613694 — 12 exons

Exon	Start	End
ENSE00002390697	43758951	43759016
ENSE00003477466	43768103	43768272
ENSE00003482972	43778193	43778302
ENSE00003499350	43777630	43777744
ENSE00003504750	43783662	43783724
ENSE00003542427	43771220	43771365
ENSE00003550861	43782307	43782490
ENSE00003572936	43773965	43774029
ENSE00003594588	43786399	43786557
ENSE00003626903	43772912	43773072
ENSE00003651866	43772180	43772362
ENSE00003725751	43786680	43789541

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 94.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.3931 / max 265.9175, expressed in 1789 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125119	16.3403	1789
125118	0.0529	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	94.15	gold quality
mononuclear cell	CL:0000842	93.67	gold quality
leukocyte	CL:0000738	93.37	gold quality
body of pancreas	UBERON:0001150	91.69	gold quality
granulocyte	CL:0000094	91.28	gold quality
rectum	UBERON:0001052	89.88	gold quality
gall bladder	UBERON:0002110	89.16	gold quality
lymph node	UBERON:0000029	89.01	gold quality
blood	UBERON:0000178	88.87	gold quality
pancreas	UBERON:0001264	88.52	gold quality
calcaneal tendon	UBERON:0003701	88.26	gold quality
spleen	UBERON:0002106	88.15	gold quality
vermiform appendix	UBERON:0001154	88.04	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.59	gold quality
mucosa of stomach	UBERON:0001199	86.70	gold quality
descending thoracic aorta	UBERON:0002345	86.69	gold quality
islet of Langerhans	UBERON:0000006	86.68	gold quality
body of stomach	UBERON:0001161	86.43	gold quality
esophagus mucosa	UBERON:0002469	86.13	gold quality
skin of abdomen	UBERON:0001416	85.83	gold quality
small intestine	UBERON:0002108	85.82	gold quality
minor salivary gland	UBERON:0001830	85.71	gold quality
right lung	UBERON:0002167	85.51	gold quality
metanephros cortex	UBERON:0010533	85.31	gold quality
right lobe of thyroid gland	UBERON:0001119	85.22	gold quality
skin of leg	UBERON:0001511	85.10	gold quality
right coronary artery	UBERON:0001625	85.07	gold quality
left lobe of thyroid gland	UBERON:0001120	85.05	gold quality
esophagus	UBERON:0001043	84.94	gold quality
stomach	UBERON:0000945	84.84	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

94 targeting IRAK4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• a novel member of the IRAK family with the properties of an IRAK-kinase (PMID:11960013)
• Gene targeting studies show that IRAK-4 has an essential role in mediating signals initiated by IL-1R and TLR engagement. Review. (PMID:12297423)
• Pellino 1 is required for interleukin-1-mediated signaling through its interaction with the interleukin-1 receptor-associated kinase 4-IRAK-tumor necrosis factor receptor-associated factor 6 complex (PMID:12496252)
• described 3 children with inherited IRAK-4 deficiency who developed pyogenic bacterial infections; findings suggest the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but redundant against most other microorganisms (PMID:12637671)
• Pellino2 interacts with kinase-active as well as kinase-inactive IRAK1 and IRAK4 (PMID:12860405)
• Results suggest that IRAK-4 is pivotal in the development of a normal inflammatory response initiated by bacterial or nonbacterial insults. (PMID:12925671)
• IRAK4 is required for the efficient recruitment of IRAK to the IL-1 receptor complex (PMID:15084582)
• IRAK-4 is an integral part of the IL-1R signaling cascade and is capable of transmitting signals both dependent on and independent of its kinase activity (PMID:15292196)
• Systemic shigellosis in a person with a primary immunodeficiency, expanding the spectrum of infections associated with IRAK-4 deficiency is reported. (PMID:15825022)
• This study demonstrates several mechanisms by which overexpression of truncated, kinase-deficient forms of IRAK-4 in a patient with recurrent bacterial infections may disrupt signaling induced by lipopolysaccharide or IL-1. (PMID:15905496)
• The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans (PMID:16286015)
• Although each system seems to possess distinct activation mechanisms, interleukin-1 receptor-associated kinase (IRAK)-4 is essential for NF-kappaB activation in Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. (PMID:17046325)
• The present data indicate that the kinase activity of IRAK-4 is dependent on the autophosphorylations at T342, T345, and S346 in the activation loop. (PMID:17141195)
• crystallographic analysis of IRAK-4 kinase in complex with inhibitors (PMID:17161373)
• We conclude that IRAK-4 phosphorylates p47phox and regulates NADPH oxidase activation after LPS stimulation. (PMID:17217339)
• IL-1RAcP, MyD88, and IRAK-4 are the stable components of the endogenous type I interleukin-1 (IL-1) receptor signaling complex (PMID:17507369)
• ST2825 interfered with recruitment of IRAK1 and IRAK4 by MyD88, causing inhibition of IL-1beta-mediated activation of NF-kappaB transcriptional activity. (PMID:17548806)
• kinase-inactive IRAK proteins can associate with Pellino proteins, thus excluding the possibility that their inability to regulate Pellino degradation is due to lack of association with the Pellino proteins (PMID:17675297)
• suggest the existence of an IRAK-4-independent TLR9-induced transduction pathway leading to PI3K activation (PMID:17878374)
• IRAK-4-dependent human Toll-like receptors appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria (PMID:17893200)
• Inherited human IRAK-4 deficiency, a recently described primary immunodeficiency leading to recurrent, invasive, pyogenic bacteria infection, and invasive pneumococcal disease in particular, is reviewed. (PMID:17917042)
• Pellino isoforms may be the E3 ubiquitin ligases that mediate the IL-1-stimulated formation of K63-pUb-IRAK1 in cells, which may contribute to activation of IKKbeta and transcription factor NF-kappaB, as well as signalling pathways dependent on IRAK1/4 (PMID:17997719)
• These results suggested that the expression of IRAK-4 alone is sufficient to cause the degradation of IRAK-1; the autophosphorylation of IRAK-1 is not necessary to terminate the TLR-induced activation of NF-kappaB. (PMID:18079163)
• Two cases of IRAK-4 deficiency that presented with unusual S. aureus infections that were not accompanied by the expected constitutional symptoms or hematologic and acute phase responses are reported. (PMID:18174872)
• These results demonstrate that downregulation of IRAK-4 requires activation of the MyD88-dependent pathway and that the death domains of both MyD88 and IRAK-4 are important for this downregulation. (PMID:18503546)
• IRAK-4-, MyD88-, and UNC-93B-deficient patients did not display autoreactive antibodies in their serum or develop autoimmune diseases, suggesting that IRAK-4, MyD88, and UNC-93B pathway blockade may thwart autoimmunity in humans. (PMID:19006693)
• patients with congenital deficiencies show enhanced susceptibility to pyogenic bacteria such as Staphylococcus or Pneumococcus (PMID:19120481)
• In human cells the non-kinase functions of IRAK-4 are essential, whereas the kinase activity of IRAK-4 appears redundant with that of IRAK-1. (PMID:19181383)
• These results demonstrate a clear association between polymorphisms in the IRAK4 gene and serum IgE levels in patients with chronic rhinosinusitis and asthma (PMID:19254290)
• analysis of an oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4 (PMID:19592493)
• IRAK-4, which is essential for virtually all TLR signalling, was suppressed, whereas the precursor for the antibiotic peptide Dermcidin was up-regulated in HIV-infected cells. (PMID:19703016)
• A detailed kinetic characterization of the phosphoryl transfer activity of IRAK-4 toward a peptide substrate derived from the activation loop of IRAK-1 is described. IRAK-4 obeys a sequential kinetic pathway. (PMID:20104875)
• Data demonstrate that the vast majority of LPS-responsive genes in IRAK4-deficient monocytes were greatly suppressed, an observation that is consistent with the described role for IRAK4 as an essential component of TLR4 signalling. (PMID:20105294)
• Mal is a substrate for IRAK1 and IRAK4 with phosphorylation promoting ubiquitination and degradation of Mal, which may serve to negatively regulate signaling by TLR2 and TLR4 (PMID:20400509)
• the crystal structure of the MyD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs (PMID:20485341)
• IRAK-4-deficient patients have defects in T-cell activation. (PMID:20621347)
• Two variants found in the MyD88 death domain, S34Y and R98C, showed severely reduced NF-kappaB activation due to reduced homo-oligomerization and IRAK4 interaction (PMID:20966070)
• Although IRAK4 kinase activity is essential for human plasmacytoid dendritic cell activation, it is dispensable in B, T, dendritic, and monocytic cells, which is in contrast with an essential active kinase role in comparable mouse cell types. (PMID:21160042)
• These results indicate that IL-1beta-induced IL-6 production in A549 cells is mediated by both PI3K and IRAK4 and suggest that involvement of PI3K in the IL-1-induced IL-6 production is cell type specific. (PMID:21166654)
• evidence that the structure-function similarities that we have identified between LYK3 and IRAK-4 may be more widely applicable to plant RLKs in general. (PMID:21205819)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	irak4	ENSDARG00000100534
mus_musculus	Irak4	ENSMUSG00000059883
rattus_norvegicus	Irak4	ENSRNOG00000005965

Paralogs (4): IRAK3 (ENSG00000090376), IRAK2 (ENSG00000134070), HASPIN (ENSG00000177602), IRAK1 (ENSG00000184216)

Protein

Protein identifiers

Interleukin-1 receptor-associated kinase 4 — Q9NWZ3 (reviewed: Q9NWZ3)

Alternative names: Renal carcinoma antigen NY-REN-64

All UniProt accessions (7): A0A8Q3SIT8, A0A8Q3SIY0, Q9NWZ3, F8VR40, F8VVZ1, F8VW24, Q69FE3

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subunit / interactions. Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome. Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor-associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Interacts with IL1RL1. Interacts (when phosphorylated) with IRAK1. May interact (when phosphorylated) with IRAK3.

Subcellular location. Cytoplasm.

Post-translational modifications. Phosphorylated.

Disease relevance. Immunodeficiency 67 (IMD67) [MIM:607676] An autosomal recessive primary immunodeficiency characterized by recurrent, life-threatening systemic and invasive bacterial infections beginning in infancy or early childhood. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NWZ3-1	1	yes
Q9NWZ3-2	2

RefSeq proteins (13): NP_001107654, NP_001138728, NP_001138729, NP_001138730, NP_001338267, NP_001338268, NP_001338269, NP_001338270, NP_001338271, NP_001338272, NP_001338273, NP_001338274, NP_057207* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR017428	IRAK4	Family
IPR037970	IRAK4_Death	Domain
IPR051824	LRR_Rcpt-Like_S/T_Kinase	Family

Pfam: PF07714

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (76 total): helix 24, strand 16, sequence variant 11, modified residue 5, sequence conflict 5, turn 5, binding site 4, domain 2, chain 1, splice variant 1, mutagenesis site 1, active site 1

Structure

Experimental structures (PDB)

96 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6EGE	X-RAY DIFFRACTION	1.4
9NA5	X-RAY DIFFRACTION	1.73
6UYA	X-RAY DIFFRACTION	1.74
8W3X	X-RAY DIFFRACTION	1.76
6O95	X-RAY DIFFRACTION	1.77
6O8U	X-RAY DIFFRACTION	1.8
8UCC	X-RAY DIFFRACTION	1.8
5UIT	X-RAY DIFFRACTION	1.84
8UCB	X-RAY DIFFRACTION	1.85
9R9K	X-RAY DIFFRACTION	1.87
9R9G	X-RAY DIFFRACTION	1.88
8SCE	X-RAY DIFFRACTION	1.89
9PSS	X-RAY DIFFRACTION	1.93
8TVN	X-RAY DIFFRACTION	1.95
8W3W	X-RAY DIFFRACTION	1.98
6O94	X-RAY DIFFRACTION	1.98
6THX	X-RAY DIFFRACTION	1.99
9NA2	X-RAY DIFFRACTION	1.99
2NRU	X-RAY DIFFRACTION	2
2OIB	X-RAY DIFFRACTION	2
6N8G	X-RAY DIFFRACTION	2
8TX0	X-RAY DIFFRACTION	2
8WTF	X-RAY DIFFRACTION	2
5UIU	X-RAY DIFFRACTION	2.02
5K75	X-RAY DIFFRACTION	2.03
6VQL	X-RAY DIFFRACTION	2.07
7QG1	X-RAY DIFFRACTION	2.07
8V2F	X-RAY DIFFRACTION	2.09
6EGD	X-RAY DIFFRACTION	2.1
6MOM	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NWZ3-F1	84.11	0.62

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): 311 (proton acceptor)

Ligand- & substrate-binding residues (4): 192–200; 213; 313–316; 329

Post-translational modifications (5): 342, 345, 346, 1, 34

Mutagenesis-validated functional residues (1):

Position	Phenotype
213	loss of kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

30 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-5603037	IRAK4 deficiency (TLR5)
R-HSA-5603041	IRAK4 deficiency (TLR2/4)
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-9020702	Interleukin-1 signaling
R-HSA-975110	TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
R-HSA-975155	MyD88 dependent cascade initiated on endosome
R-HSA-975871	MyD88 cascade initiated on plasma membrane
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade
R-HSA-199418	Negative regulation of the PI3K/AKT network
R-HSA-446652	Interleukin-1 family signaling
R-HSA-449147	Signaling by Interleukins
R-HSA-5260271	Diseases of Immune System
R-HSA-5602358	Diseases associated with the TLR signaling cascade
R-HSA-9006925	Intracellular signaling by second messengers

MSigDB gene sets: 313 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, TGCGCANK_UNKNOWN, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_TOLL_LIKE_RECEPTOR_9_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, PID_IL1_PATHWAY, chr12q12, GOCC_CELL_SURFACE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY

GO Biological Process (21): toll-like receptor signaling pathway (GO:0002224), neutrophil mediated immunity (GO:0002446), MyD88-dependent toll-like receptor signaling pathway (GO:0002755), JNK cascade (GO:0007254), Toll signaling pathway (GO:0008063), cytokine-mediated signaling pathway (GO:0019221), lipopolysaccharide-mediated signaling pathway (GO:0031663), toll-like receptor 4 signaling pathway (GO:0034142), toll-like receptor 9 signaling pathway (GO:0034162), intracellular signal transduction (GO:0035556), interleukin-33-mediated signaling pathway (GO:0038172), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), innate immune response (GO:0045087), positive regulation of smooth muscle cell proliferation (GO:0048661), interleukin-1-mediated signaling pathway (GO:0070498), neutrophil migration (GO:1990266), immune system process (GO:0002376), protein phosphorylation (GO:0006468), signal transduction (GO:0007165), positive regulation of defense response (GO:0031349), non-canonical NF-kappaB signal transduction (GO:0038061)

GO Molecular Function (11): magnesium ion binding (GO:0000287), protein serine/threonine kinase activity (GO:0004674), interleukin-1 receptor binding (GO:0005149), ATP binding (GO:0005524), kinase activity (GO:0016301), protein kinase binding (GO:0019901), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), endosome membrane (GO:0010008), extrinsic component of plasma membrane (GO:0019897)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Toll-like Receptor Cascades	5
Diseases associated with the TLR signaling cascade	2
MyD88 dependent cascade initiated on endosome	2
Toll Like Receptor 2 (TLR2) Cascade	2
Intracellular signaling by second messengers	1
Toll Like Receptor 4 (TLR4) Cascade	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Negative regulation of the PI3K/AKT network	1
Interleukin-1 family signaling	1
Toll Like Receptor 9 (TLR9) Cascade	1
Toll Like Receptor 7/8 (TLR7/8) Cascade	1
Toll Like Receptor 10 (TLR10) Cascade	1
Toll Like Receptor 5 (TLR5) Cascade	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor signaling pathway	3
cellular anatomical structure	3
intracellular anatomical structure	2
cytokine-mediated signaling pathway	2
protein kinase activity	2
pattern recognition receptor signaling pathway	1
myeloid leukocyte mediated immunity	1
toll-like receptor signaling pathway	1
MAPK cascade	1
cellular response to cytokine stimulus	1
cellular response to lipopolysaccharide	1
cell surface toll-like receptor signaling pathway	1
endolysosomal toll-like receptor signaling pathway	1
signal transduction	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
immune response	1
defense response to symbiont	1
positive regulation of cell population proliferation	1
smooth muscle cell proliferation	1
regulation of smooth muscle cell proliferation	1
cellular response to interleukin-1	1
granulocyte migration	1
biological_process	1
phosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
defense response	1
regulation of defense response	1
positive regulation of response to stimulus	1
metal ion binding	1
cytokine receptor binding	1
growth factor receptor binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

2821 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRAK4	MYD88	P78397	999
IRAK4	TRAF6	Q9Y4K3	998
IRAK4	TRAF3	Q13114	994
IRAK4	TLR4	O00206	991
IRAK4	IRAK2	O43187	989
IRAK4	IRAK1	P51617	988
IRAK4	IRF7	Q92985	964
IRAK4	IRAK3	Q9Y616	947
IRAK4	PELI1	Q96FA3	947
IRAK4	IL1R1	P14778	945
IRAK4	TLR2	O60603	927
IRAK4	TLR7	Q9NYK1	921
IRAK4	TLR8	Q9NR97	908
IRAK4	CHUK	O15111	899
IRAK4	TLR3	O15455	897
IRAK4	TIRAP	P58753	897

IntAct

69 interactions, top by confidence:

A	B	Type	Score
MYD88	IRAK4	psi-mi:“MI:0915”(physical association)	0.920
IRAK4	MYD88	psi-mi:“MI:0915”(physical association)	0.920
TLR4	TIRAP	psi-mi:“MI:0914”(association)	0.810
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
PELI1	IRAK4	psi-mi:“MI:0217”(phosphorylation reaction)	0.770
IRAK4	PELI1	psi-mi:“MI:0915”(physical association)	0.770
PELI1	IRAK4	psi-mi:“MI:0915”(physical association)	0.770
MYD88	IRAK4	psi-mi:“MI:0915”(physical association)	0.750
MYD88	IRAK4	psi-mi:“MI:0407”(direct interaction)	0.750
PELI1	IRAK1	psi-mi:“MI:0914”(association)	0.730
IRAK4	IRAK2	psi-mi:“MI:0914”(association)	0.710

BioGRID (87): IRAK4 (Two-hybrid), IRAK4 (Reconstituted Complex), IRAK4 (Affinity Capture-MS), IRAK4 (Two-hybrid), VSIG8 (Affinity Capture-MS), MYD88 (Two-hybrid), IRAK4 (Two-hybrid), IRAK4 (Two-hybrid), IRAK4 (Two-hybrid), IRAK4 (Two-hybrid), IRAK4 (Two-hybrid), RNF152 (Affinity Capture-Western), IRAK4 (Affinity Capture-RNA), VSIG8 (Affinity Capture-MS), IRAK4 (Affinity Capture-Western)

ESM2 similar proteins: A9TXT1, G5ECP4, H2KZW3, O12990, O13147, O19064, O48837, O49839, O49840, O60674, P51813, P53356, P54758, P79750, P97504, Q05652, Q05688, Q07407, Q09178, Q1RMT8, Q54RB7, Q54Y55, Q5JJY4, Q5R5V4, Q5RB23, Q5XF57, Q60629, Q62120, Q62413, Q62689, Q75R65, Q8GYF5, Q8R4K2, Q8RXC8, Q8VZJ9, Q95YD4, Q9ASQ5, Q9C6K9, Q9C823, Q9CAC3

Diamond homologs: A0A509AH51, A1CAF0, A1CL96, A1D624, A2QU77, A2YMV6, A8BPK8, B1H3E1, B5VNQ3, C4YGK0, D0Z5N4, O18209, O19004, O34507, O45797, O61661, P04627, P09251, P0CS76, P0CS77, P10398, P10533, P12965, P14056, P15056, P19026, P23293, P27966, P28028, P28926, P32516, P32866, P34908, P41808, P51953, P52304, P84390, Q00772, Q01577, Q04543

SIGNOR signaling

25 interactions.

A	Effect	B	Mechanism
IRAK4	up-regulates	PELI2	phosphorylation
IRAK4	“up-regulates activity”	IRAK1	phosphorylation
IRAK4	“up-regulates activity”	IRAK4	phosphorylation
IRAK4	up-regulates	NCF1	phosphorylation
MYD88	“up-regulates activity”	IRAK4	binding
IRAK3	down-regulates	IRAK4	binding
IL1RL1	“up-regulates activity”	IRAK4	binding
IRAK4	“up-regulates activity”	PELI1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 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:

Pathway	Partners	Fold	FDR
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	5	50.8×	4e-06
Interleukin-1 signaling	5	41.4×	5e-06

GO biological processes:

GO term	Partners	Fold	FDR
MyD88-dependent toll-like receptor signaling pathway	5	275.4×	1e-09
toll-like receptor 4 signaling pathway	5	154.9×	1e-08
positive regulation of canonical NF-kappaB signal transduction	7	29.9×	1e-07
inflammatory response	6	13.3×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	6
Uncertain significance	181
Likely benign	105
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012217	NM_016123.4(IRAK4):c.364C>T (p.Gln122Ter)	Pathogenic
1012218	NC_000012.12:g.43775405_43788500del	Pathogenic
1427828	NM_016123.4(IRAK4):c.288_304del (p.Ala97fs)	Pathogenic
1456107	NM_016123.4(IRAK4):c.1135G>T (p.Glu379Ter)	Pathogenic
1457405	NM_016123.4(IRAK4):c.1290C>G (p.Tyr430Ter)	Pathogenic
1459926	NC_000012.11:g.(?44176090)(44176313_?)del	Pathogenic
2053205	NM_016123.4(IRAK4):c.652delA (p.Met218fs)	Pathogenic
2137317	NM_016123.4(IRAK4):c.1146del (p.Gly383fs)	Pathogenic
2137318	NM_016123.4(IRAK4):c.1204G>T (p.Glu402Ter)	Pathogenic
2790034	NM_016123.4(IRAK4):c.181C>T (p.Gln61Ter)	Pathogenic
2803498	NM_016123.4(IRAK4):c.274_281dup (p.Phe94fs)	Pathogenic
2818504	NM_016123.4(IRAK4):c.629_630del (p.Val210fs)	Pathogenic
2837459	NM_016123.4(IRAK4):c.1039A>T (p.Arg347Ter)	Pathogenic
3002605	NM_016123.4(IRAK4):c.143dup (p.Tyr48Ter)	Pathogenic
3244312	NC_000012.11:g.(?44161915)(44180518_?)del	Pathogenic
3648245	NM_016123.4(IRAK4):c.554_556delinsGGGGTACATATTAGCATTTTGTACCATTATTATTGGTGCTAAAGTTTGATCACTTGGTGAAGGAAGTGTACTTCAGATTTCCTCATTAAAAATGTACCCTTCTCTTTCATACTTCACAAGTAATTTGTGTACAATACTTTTTCTCTATCTATTGAGGGGGTCTTGCTCTGTCACTCAGGCTGGAGTGCAGTGGCATGATCATGGCTCACTGCAGCCTTGACTTCCTGGGCTCAGGTGATCCTCCCACCTCAACCTCCCAAGTAGCTGGGACTACAGGCGTGCACTACCACACCCAGCTAATTTTTTGTAGTGATGGGGTTTTAC (p.Ile185_Ser186delinsArgGlyThrTyrTer)	Pathogenic
3662862	NM_016123.4(IRAK4):c.797_798del (p.Pro266fs)	Pathogenic
3838	NM_016123.4(IRAK4):c.821del (p.Leu274fs)	Pathogenic
3839	NM_016123.4(IRAK4):c.877C>T (p.Gln293Ter)	Pathogenic
3840	NM_016123.4(IRAK4):c.623_624del (p.Thr208fs)	Pathogenic
3841	NM_016123.4(IRAK4):c.1189-1G>T	Pathogenic
4076065	GRCh37/hg19 12q12(chr12:44090883-44354797)x1	Pathogenic
464933	NM_016123.4(IRAK4):c.224del (p.Gly75fs)	Pathogenic
533523	NM_016123.4(IRAK4):c.88G>T (p.Glu30Ter)	Pathogenic
846951	NM_016123.4(IRAK4):c.869_885del (p.Lys290fs)	Pathogenic
853817	NM_016123.4(IRAK4):c.781del (p.Val261fs)	Pathogenic
858438	NM_016123.4(IRAK4):c.518T>A (p.Leu173Ter)	Pathogenic
870469	NM_016123.4(IRAK4):c.1049del (p.Gly350fs)	Pathogenic
929845	NM_016123.4(IRAK4):c.524del (p.Asn175fs)	Pathogenic
929846	NM_016123.4(IRAK4):c.123dup (p.Pro42fs)	Pathogenic

SpliceAI

2278 predictions. Top by Δscore:

Variant	Effect	Δscore
12:43765376:A:AG	donor_gain	1.0000
12:43768097:TTTTA:T	acceptor_loss	1.0000
12:43768098:TTTA:T	acceptor_loss	1.0000
12:43768099:TTAG:T	acceptor_loss	1.0000
12:43768100:TAG:T	acceptor_loss	1.0000
12:43768101:A:AG	acceptor_gain	1.0000
12:43768102:G:GG	acceptor_gain	1.0000
12:43768102:GGA:G	acceptor_gain	1.0000
12:43768268:ATAAG:A	donor_loss	1.0000
12:43768269:TAAGG:T	donor_loss	1.0000
12:43768270:AAG:A	donor_loss	1.0000
12:43768271:AGGTA:A	donor_loss	1.0000
12:43768272:GGTAA:G	donor_loss	1.0000
12:43768273:G:GC	donor_loss	1.0000
12:43768274:T:A	donor_loss	1.0000
12:43770990:A:AG	acceptor_gain	1.0000
12:43771212:C:G	acceptor_gain	1.0000
12:43771217:A:AG	acceptor_gain	1.0000
12:43771217:AAG:A	acceptor_gain	1.0000
12:43771218:A:G	acceptor_gain	1.0000
12:43771219:GGA:G	acceptor_gain	1.0000
12:43771306:ATCTT:A	donor_gain	1.0000
12:43772175:GTTA:G	acceptor_loss	1.0000
12:43772176:TTA:T	acceptor_loss	1.0000
12:43772178:A:AG	acceptor_gain	1.0000
12:43772178:A:C	acceptor_loss	1.0000
12:43772179:G:GG	acceptor_gain	1.0000
12:43772179:G:GT	acceptor_loss	1.0000
12:43772343:TTTAG:T	donor_gain	1.0000
12:43772358:TACAC:T	donor_gain	1.0000

AlphaMissense

3059 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:43768205:T:A	W32R	1.000
12:43768205:T:C	W32R	1.000
12:43773010:T:C	F197L	1.000
12:43773012:T:A	F197L	1.000
12:43773012:T:G	F197L	1.000
12:43773060:G:C	K213N	1.000
12:43773060:G:T	K213N	1.000
12:43778293:A:C	D311A	1.000
12:43778293:A:T	D311V	1.000
12:43778298:A:G	K313E	1.000
12:43778299:A:T	K313I	1.000
12:43778300:A:C	K313N	1.000
12:43778300:A:T	K313N	1.000
12:43782350:G:C	D329H	1.000
12:43782351:A:C	D329A	1.000
12:43782351:A:T	D329V	1.000
12:43782352:C:A	D329E	1.000
12:43782352:C:G	D329E	1.000
12:43771309:T:C	L84P	0.999
12:43773014:G:A	G198E	0.999
12:43773053:C:A	A211E	0.999
12:43773058:A:C	K213Q	0.999
12:43773058:A:G	K213E	0.999
12:43778286:C:G	H309D	0.999
12:43778290:G:C	R310T	0.999
12:43778290:G:T	R310I	0.999
12:43778292:G:C	D311H	0.999
12:43778293:A:G	D311G	0.999
12:43778294:T:A	D311E	0.999
12:43778294:T:G	D311E	0.999

dbSNP variants (sampled 300 via entrez): RS1000073046 (12:43762431 T>C), RS1000225908 (12:43789066 A>G), RS1000254394 (12:43779419 C>T), RS1000331325 (12:43782656 A>G), RS1000379648 (12:43785711 T>C), RS1000412298 (12:43785464 C>T), RS1000440239 (12:43776287 A>G), RS1000582055 (12:43788846 A>G), RS1000725542 (12:43779135 A>G), RS1000785770 (12:43782945 A>G), RS1000879713 (12:43766803 T>C), RS1000989218 (12:43780814 G>A,T), RS1000991467 (12:43770736 T>C,G), RS1001110592 (12:43774398 C>A), RS1001144917 (12:43774104 G>A)

Disease associations

OMIM: gene MIM:606883 | disease phenotypes: MIM:607676, MIM:224120

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 67	Strong	Autosomal recessive

Mondo (2): immunodeficiency 67 (MONDO:0011888), congenital dyserythropoietic anemia (MONDO:0019403)

Orphanet (2): Transient predisposition to invasive pyogenic bacterial infection (Orphanet:70592), Congenital dyserythropoietic anemia (Orphanet:85)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001287	Meningitis
HP:0001875	Decreased total neutrophil count
HP:0001945	Fever
HP:0002718	Recurrent bacterial infections
HP:0002721	Immunodeficiency
HP:0003095	Septic arthritis
HP:0003212	Increased circulating IgE concentration
HP:0003593	Infantile onset
HP:0005366	Recurrent streptococcus pneumoniae infections
HP:0005406	Recurrent bacterial skin infections
HP:0007499	Recurrent staphylococcal infections
HP:0010975	Abnormal B cell count
HP:0011463	Childhood onset
HP:0011839	Abnormal total T cell count
HP:0020096	Recurrent streptococcal infections
HP:0040089	Abnormal total natural killer cell count
HP:0100523	Liver abscess
HP:0410255	Transiently decreased total neutrophil count
HP:0410300	Complete or near-complete absence of specific antibody response to unconjugated pneumococcus vaccine

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001536_6	Immune reponse to smallpox (secreted TNF-alpha)	2.000000e-08
GCST003602_9	Inflammatory bowel disease	6.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000742	Anemia, Dyserythropoietic, Congenital	C15.378.050.141.150.095; C16.320.070.095
C564352	IRAK4 Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL3778 (SINGLE PROTEIN), CHEMBL4523710 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523723 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523742 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

43 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 345,818 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL939	GEFITINIB	4	117,814
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL3544983	TESEVATINIB	3	2,819
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL1738757	REBASTINIB	2	1,478
CHEMBL1822792	MK-2461	2
CHEMBL1967878	CENISERTIB	2
CHEMBL1980297	ILORASERTIB	2
CHEMBL1980715	LAUROGUADINE	2
CHEMBL2386889	SCH-900776	2
CHEMBL4081711	ZIMLOVISERTIB	2
CHEMBL4094440	BMS-919373	2
CHEMBL475251	R-406	2
CHEMBL4783351	EMAVUSERTIB	2
CHEMBL513909	BI-2536	2

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 (18 total), top 18:

Ligand	Action	Affinity	Parameter
BIO-8169	Inhibition	9.7	pIC50
zimlovisertib	Inhibition	9.7	pIC50
PF-06426779	Inhibition	9.52	pIC50
BIO-7488	Inhibition	9.22	pIC50
edecesertib	Inhibition	9.0	pIC50
IRAK4 inhibitor rac-45 [PMID: 18501603]	Inhibition	9.0	pIC50
ND-2158	Inhibition	9.0	pKi
compound 1 [WO2012007375]	Inhibition	9.0	pIC50
BAY1830839	Inhibition	8.52	pIC50
nacresertib	Inhibition	8.22	pIC50
GLPG2534	Inhibition	8.19	pIC50
ND-2110	Inhibition	8.12	pKi
compound 7 [WO2012007375]	Inhibition	8.1	pIC50
zabedosertib	Inhibition	7.97	pIC50
IRAK4 inhibitor 4b [PMID: 18474425]	Inhibition	7.7	pIC50
emavusertib	Inhibition	7.5	pIC50
Takinib	Inhibition	6.92	pIC50
IRAK-1/4 inhibitor	Inhibition	6.7	pIC50

Binding affinities (BindingDB)

4776 measured of 6095 human assays (6100 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-3-methoxy-2-naphthamide	IC50	0.1 nM	US-10174000: Bicyclic-fused heteroaryl or aryl compounds as IRAK4 modulators
1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy]-4-fluoro-7-methoxyisoquinoline-6-carboxamide	IC50	0.1 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
1-[[(2S,3S,4S)-4-fluoro-3-(2-fluoroethyl)-5-oxopyrrolidin-2-yl]methoxy]-7-methoxyisoquinoline-6-carboxamide	IC50	0.1 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
2-[(3R)- or (3S)-azepan- 3-ylamino]-N-[3- (difluoromethyl)-1- methyl-1H-pyrazol-4- yl]pyrrolo[1,2- b]pyridazine-7- carboxamide trifluoroacetate	IC50	0.2 nM	US-10040798: Pyrrolopyridazine inhibitors of IRAK4 activity
2[(3R)-3- aminopiperidin-1-yl] N-[3-(difluoromethyl)- 1-methyl-1H-pyrazol- 4-yl]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate	IC50	0.2 nM	US-10040802: Thienopyrazine inhibitors of IRAK4 activity
2-{[(1R,2S)-2- aminocyclohexyl]amino}- N-[3-(difluoromethyl)- 1-methyl-1H-pyrazol- 4-yl]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate	IC50	0.2 nM	US-10040802: Thienopyrazine inhibitors of IRAK4 activity
2-[(3S)- or (3R)- azepan-3-ylamino]-N- [3-(difluoromethyl)-1- methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate	IC50	0.2 nM	US-10040802: Thienopyrazine inhibitors of IRAK4 activity
(1R,2S,3R,5S)-3-[[2-[(2,6-dimethyl-4-pyridinyl)amino]-5-quinolin-2-ylpyrimidin-1-ium-4-yl]amino]-5-(2-hydroxypropan-2-yl)cyclopentane-1,2-diol	IC50	0.2 nM	US-9598440: Inhibitors of IRAK4 activity
(1R,2S,3R,5S)-3-[[5-(1,3-benzothiazol-2-yl)-2-[(2,6-dimethyl-4-pyridinyl)amino]pyrimidin-1-ium-4-yl]amino]-5-(2-hydroxypropan-2-yl)cyclopentane-1,2-diol	IC50	0.2 nM	US-9598440: Inhibitors of IRAK4 activity
(1S,2R,3S,5R)-3-(2-hydroxypropan-2-yl)-5-[[2-[(2-methyl-4-pyridinyl)amino]-5-quinolin-2-ylpyrimidin-1-ium-4-yl]amino]cyclopentane-1,2-diol	IC50	0.2 nM	US-9598440: Inhibitors of IRAK4 activity
(1R,2S,3R,5S)-3-[[2-[(2,6-dimethyl-4-pyridinyl)amino]-5-(4-methyl-1,3-thiazol-2-yl)pyrimidin-4-yl]amino]-5-(2-hydroxypropan-2-yl)cyclopentane-1,2-diol	IC50	0.2 nM	US-9598440: Inhibitors of IRAK4 activity
(1R,2S,3R,5S)-3-[[2-[(2,6-dimethyl-4-pyridinyl)amino]-5-([1,3]thiazolo[4,5-c]pyridin-5-ium-2-yl)pyrimidin-4-yl]amino]-5-(2-hydroxypropan-2-yl)cyclopentane-1,2-diol	IC50	0.2 nM	US-9598440: Inhibitors of IRAK4 activity
1-[[(2S)-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy]-7-methoxyisoquinoline-6-carboxamide	IC50	0.2 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
1-[[(2S,3S)-4,4-difluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy]-7-propan-2-yloxyisoquinoline-6-carboxamide	IC50	0.2 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
4-[[(1R,2S,5S,6S)-5-fluoro-6-methyl-4-oxo-3-azabicyclo[3.1.0]hexan-2-yl]methoxy]-6-methoxyquinoline-7-carboxamide	IC50	0.2 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
1-[[(2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy]-7-methoxyisoquinoline-6-carboxamide	IC50	0.2 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
2-[(3R)- or (3S)-azepan- 3-ylamino]-N-[3- (difluoromethyl)-1- methyl-1H-pyrazol-4- yl]pyrrolo[1,2- b]pyridazine-7- carboxamide trifluoroacetate	IC50	0.3 nM	US-10040798: Pyrrolopyridazine inhibitors of IRAK4 activity
2-{[(1R,2S)-2- aminocyclohexyl]amino}- N-(3-chloro-1- methyl-1H-pyrazol- 4-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate	IC50	0.3 nM	US-10040802: Thienopyrazine inhibitors of IRAK4 activity
4-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-6-methoxyisoquinoline-7-carboxamide	IC50	0.3 nM	US-10174000: Bicyclic-fused heteroaryl or aryl compounds as IRAK4 modulators
5-[[(1R,2S)-2-aminocyclohexyl]amino]-N-(3-bromo-1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.3 nM	US-10329294: Pyrazolopyrimidine inhibitors of IRAK4 activity
1-[[(2S)-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy]-7-propan-2-yloxyisoquinoline-6-carboxamide	IC50	0.3 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
5-[[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy]-3-methoxynaphthalene-2-carboxamide	IC50	0.3 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
3-methoxy-5-[[(4R)-2-oxo-1,3-oxazolidin-4-yl]methoxy]naphthalene-2-carboxamide	IC50	0.3 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
4-[[(1R,2S,5S,6S)-6-(fluoromethyl)-4-oxo-3-azabicyclo[3.1.0]hexan-2-yl]methoxy]-6-methoxyquinoline-7-carboxamide	IC50	0.3 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
1-[[(1S,2S,5R,6R)-6-fluoro-6-methyl-4-oxo-3-azabicyclo[3.1.0]hexan-2-yl]methoxy]-7-methoxyisoquinoline-6-carboxamide	IC50	0.3 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
4-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy]-6-methoxyquinazoline-7-carboxamide	IC50	0.3 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
1-[[(2S,3S,4S)-3-cyclopropyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy]-7-methoxyisoquinoline-6-carboxamide	IC50	0.3 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
1-[[(2S,3R,4R)-4-fluoro-3-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy]-7-methoxyisoquinoline-6-carboxamide	IC50	0.3 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
2-{[(1R,2S)-2- aminocyclohexyl]amino}- N-(3-cyano-1- methyl-1H-pyrazol- 4-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate	IC50	0.4 nM	US-10040802: Thienopyrazine inhibitors of IRAK4 activity
5-[[(1R,2S)-2-aminocyclohexyl]amino]-N-[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.4 nM	US-10329294: Pyrazolopyrimidine inhibitors of IRAK4 activity
1-[[(2S,4S)-4-fluoro-5-oxopyrrolidin-2-yl]methoxy]-7-propan-2-yloxyisoquinoline-6-carboxamide	IC50	0.4 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
1-[[(2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy]-7-propan-2-yloxyisoquinoline-6-carboxamide	IC50	0.4 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
3-methoxy-5-[[(2S,3R)-3-methyl-5-oxopyrrolidin-2-yl]methoxy]naphthalene-2-carboxamide	IC50	0.4 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
4-[[(1R,2S,5S)-5-fluoro-4-oxo-3-azabicyclo[3.1.0]hexan-2-yl]methoxy]-6-methoxyquinoline-7-carboxamide	IC50	0.4 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy]-7-propan-2-yloxyisoquinoline-6-carboxamide	IC50	0.4 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
7-ethoxy-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy]isoquinoline-6-carboxamide	IC50	0.4 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
1-[[(2S,3R,4S)-4-fluoro-3-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy]-7-methoxyisoquinoline-6-carboxamide	IC50	0.4 nM	US-10329302: Bicyclic-fused heteroaryl or aryl compounds
4-(cyclopropylamino)-N-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-6-([1,3]thiazolo[5,4-b]pyridin-5-ylamino)pyridine-3-carboxamide	IC50	0.5 nM	US-9546153: Bicyclic heterocycle substituted pyridyl compounds useful as kinase modulators
2-[(3R)-3- aminopiperidin-1-yl]-N- [1-methyl-3- (trifluoromethyl)-1H- pyrazol-4- yl]pyrrolo[1,2- b]pyridazine-7- carboxamide trifluoroacetate	IC50	0.5 nM	US-10040798: Pyrrolopyridazine inhibitors of IRAK4 activity
2-[(3R)-3- aminopiperidin-1-yl]-N- [3-(difluoromethyl)-1- methyl-1H-pyrazol-4- yl]pyrrolo[1,2- b]pyridazine-7- carboxamide trifluoroacetate	IC50	0.5 nM	US-10040798: Pyrrolopyridazine inhibitors of IRAK4 activity
2-(3,8- diazabicyclo[3.2.1] oct-8-yl)-N-[3- (difluoromethyl)-1- methyl-1H-pyrazol-4- yl]thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate	IC50	0.5 nM	US-10040802: Thienopyrazine inhibitors of IRAK4 activity
2-{[(1R,2S)-2-amino- cyclohexyl]amino}- N-(4-cyanothiophen- 3-yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate	IC50	0.5 nM	US-10040802: Thienopyrazine inhibitors of IRAK4 activity
2-{[(1R,2S)-2-amino- cyclohexyl]amino}- N-(2-(cyanothiophen-3- yl)thieno[2,3-b] pyrazine-7- carboxamide trifluoroacetate	IC50	0.5 nM	US-10040802: Thienopyrazine inhibitors of IRAK4 activity
2-{[(1R,2S)-2- aminocyclohexyl]- amino}-N-(2- cyanophenyl)- thieno[2,3-b]- pyrazine-7- carboxamide trifluoroacetate	IC50	0.5 nM	US-10040802: Thienopyrazine inhibitors of IRAK4 activity
(1R,2S,3R,5R)-3-[[2-[(2,6-dimethyl-4-pyridinyl)amino]-5-([1,3]thiazolo[4,5-c]pyridin-2-yl)pyrimidin-4-yl]amino]-5-(hydroxymethyl)cyclopentane-1,2-diol	IC50	0.5 nM	US-9598440: Inhibitors of IRAK4 activity
(1R,2S,3R,5S)-3-[[2-[(2,6-dimethyl-4-pyridinyl)amino]-5-(4-methyl-[1,3]thiazolo[4,5-c]pyridin-2-yl)pyrimidin-1-ium-4-yl]amino]-5-(2-hydroxypropan-2-yl)cyclopentane-1,2-diol	IC50	0.5 nM	US-9598440: Inhibitors of IRAK4 activity
4-Amino-1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide	IC50	0.5 nM	US-10174000: Bicyclic-fused heteroaryl or aryl compounds as IRAK4 modulators
N-[3-(difluoromethyl)-1-methylpyrazol-4-yl]-5-[(3R)-3-hydroxypiperidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.5 nM	US-10329294: Pyrazolopyrimidine inhibitors of IRAK4 activity
N-[3-(difluoromethyl)-1-methylpyrazol-4-yl]-5-[(3S)-3-hydroxypiperidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.5 nM	US-10329294: Pyrazolopyrimidine inhibitors of IRAK4 activity
5-[(3R)-3-aminopiperidin-1-yl]-N-[3-(difluoromethyl)-1-methylpyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	0.5 nM	US-10329294: Pyrazolopyrimidine inhibitors of IRAK4 activity

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.66	IC50	0.022	nM	CHEMBL4443947
10.59	IC50	0.026	nM	CHEMBL4556091
10.11	IC50	0.078	nM	CHEMBL4566431
10.09	IC50	0.081	nM	CHEMBL4545898
10.02	Kd	0.096	nM	CHEMBL6078253
10.02	IC50	0.096	nM	CHEMBL6077980
10.00	IC50	0.1	nM	CHEMBL4066705
10.00	IC50	0.1	nM	CHEMBL4445098
10.00	IC50	0.099	nM	CHEMBL4448950
10.00	IC50	0.1	nM	CHEMBL5190644
10.00	IC50	0.1	nM	CHEMBL5646411
10.00	IC50	0.1	nM	CHEMBL4520946
10.00	IC50	0.1	nM	CHEMBL6030179
10.00	IC50	0.1	nM	CHEMBL6034612
10.00	IC50	0.1	nM	ZIMLOVISERTIB
9.96	IC50	0.11	nM	CHEMBL4568894
9.85	Kd	0.14	nM	CHEMBL5561819
9.80	IC50	0.16	nM	CHEMBL4472406
9.80	IC50	0.16	nM	CHEMBL5542730
9.77	IC50	0.17	nM	CHEMBL5549771
9.77	IC50	0.17	nM	CHEMBL5564777
9.72	IC50	0.19	nM	CHEMBL4475494
9.72	IC50	0.19	nM	CHEMBL5532502
9.72	IC50	0.19	nM	CHEMBL5517690
9.70	IC50	0.2	nM	CHEMBL3590479
9.70	IC50	0.2	nM	CHEMBL3634383
9.70	IC50	0.2	nM	CHEMBL3634510
9.70	IC50	0.2	nM	ZIMLOVISERTIB
9.70	IC50	0.2	nM	CHEMBL4520946
9.70	IC50	0.2	nM	CHEMBL5202941
9.70	IC50	0.2	nM	CHEMBL5176061
9.70	IC50	0.2	nM	CHEMBL5196239
9.70	IC50	0.2	nM	CHEMBL5567925
9.70	IC50	0.2	nM	CHEMBL5563121
9.70	IC50	0.2	nM	CHEMBL5567653
9.70	IC50	0.2	nM	CHEMBL5568243
9.70	IC50	0.2	nM	CHEMBL5639259
9.70	IC50	0.2	nM	CHEMBL5647518
9.70	IC50	0.2	nM	CHEMBL6060552
9.70	IC50	0.2	nM	CHEMBL5829402
9.70	IC50	0.2	nM	CHEMBL5762417
9.70	IC50	0.2	nM	CHEMBL5851954
9.70	IC50	0.2	nM	CHEMBL3403457
9.70	IC50	0.2	nM	CHEMBL5905777
9.70	IC50	0.2	nM	CHEMBL5859339
9.70	IC50	0.2	nM	CHEMBL5840141
9.70	IC50	0.2	nM	CHEMBL5973436
9.70	IC50	0.2	nM	CHEMBL5939326
9.70	IC50	0.2	nM	CHEMBL5766517
9.70	IC50	0.2	nM	CHEMBL5959400

PubChem BioAssay actives

1607 with measured affinity, of 3989 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.

Compound	Assay	Type	Value	Unit
N-[6-[4-(azetidin-1-yl)piperidin-1-yl]-2-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-1-oxo-3H-isoindol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1547741: Inhibition of IRAK4 in human whole blood assessed as inhibition of R848-induced IL-6 production preincubated for 90 mins followed by R848 stimulation and measured after 3.5 hrs by MSD assay	ic50	<0.0001	uM
4-[3-[2-[2-[3-[[(3S,5S)-1-[(2S)-2-cyclohexyl-2-[[(2S)-2-(methylamino)propanoyl]amino]acetyl]-5-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]carbamoyl]pyrrolidin-3-yl]amino]-3-oxopropoxy]ethoxy]ethoxy]prop-1-ynyl]-7-methoxy-1-[[(2S)-5-oxopyrrolidin-2-yl]methoxy]isoquinoline-6-carboxamide	1564077: Binding affinity to human IRK4 using myelin basic protein as substrate by [gamma-33P]-ATP assay	ic50	<0.0001	uM
2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-N-imidazo[1,2-b]pyridazin-3-yl-6-(3-methoxycyclobutyl)oxyindazole-5-carboxamide	1886982: Inhibition of recombinant human full-length His-tagged IRAK4 expressed in baculovirus infected insect cells using KKARFSRFAGSSPSQSSMVAR as substrate preincubated for 15 mins followed by substrate addition and measured after 2 hrs by LC-MS/MS analysis	ic50	<0.0001	uM
1-[[(2S,3S,4R)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy]-7-methoxyisoquinoline-6-carboxamide	1448131: Inhibition of N-terminal His6-tagged human full length IRAK4 preincubated for 20 mins followed by biotinylated-AGAGRDKYKTLRQIR substrate addition in presence of ATP measured after 60 mins by DELFIA method	ic50	0.0001	uM
N-[6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-1-oxo-3H-isoindol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1547741: Inhibition of IRAK4 in human whole blood assessed as inhibition of R848-induced IL-6 production preincubated for 90 mins followed by R848 stimulation and measured after 3.5 hrs by MSD assay	ic50	0.0001	uM
N-[6-[4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl]-2-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-1-oxo-3H-isoindol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1547741: Inhibition of IRAK4 in human whole blood assessed as inhibition of R848-induced IL-6 production preincubated for 90 mins followed by R848 stimulation and measured after 3.5 hrs by MSD assay	ic50	0.0001	uM
N-[6-[4-(3,3-difluorocyclobutyl)piperazin-1-yl]-2-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-1-oxo-3H-isoindol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1547741: Inhibition of IRAK4 in human whole blood assessed as inhibition of R848-induced IL-6 production preincubated for 90 mins followed by R848 stimulation and measured after 3.5 hrs by MSD assay	ic50	0.0001	uM
N-[2-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-6-[4-(oxetan-3-yl)piperazin-1-yl]-1-oxo-3H-isoindol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1547741: Inhibition of IRAK4 in human whole blood assessed as inhibition of R848-induced IL-6 production preincubated for 90 mins followed by R848 stimulation and measured after 3.5 hrs by MSD assay	ic50	0.0001	uM
4-[13-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-13-oxotridec-1-ynyl]-7-methoxy-1-[[(2S)-5-oxopyrrolidin-2-yl]methoxy]isoquinoline-6-carboxamide	1564077: Binding affinity to human IRK4 using myelin basic protein as substrate by [gamma-33P]-ATP assay	ic50	0.0001	uM
N-imidazo[1,2-b]pyridazin-3-yl-6-methoxy-2-(1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)indazole-5-carboxamide	1886982: Inhibition of recombinant human full-length His-tagged IRAK4 expressed in baculovirus infected insect cells using KKARFSRFAGSSPSQSSMVAR as substrate preincubated for 15 mins followed by substrate addition and measured after 2 hrs by LC-MS/MS analysis	ic50	0.0001	uM
N-[1-[(1S,2R)-2-fluorocyclopropyl]-2-oxo-3-pyridinyl]-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-6-propan-2-yloxypyrazolo[3,4-b]pyridine-5-carboxamide	2144571: Inhibition of IRAK4 (unknown origin) incubated for 1 hr in presence of ATP by Mesoscale assay	ic50	0.0001	uM
N-[2-[4-[[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]butyl-methylamino]methyl]cyclohexyl]-6-(2-hydroxypropan-2-yl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide	2085323: Binding affinity to CRBN/IRAK4 in human OCI-Ly10 cells assessed as dissociation constant by DiscoverX Kd Elect assay	kd	0.0001	uM
1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy]-7-methoxyisoquinoline-6-carboxamide	1448131: Inhibition of N-terminal His6-tagged human full length IRAK4 preincubated for 20 mins followed by biotinylated-AGAGRDKYKTLRQIR substrate addition in presence of ATP measured after 60 mins by DELFIA method	ic50	0.0002	uM
N-(3-carbamoyl-1-methylpyrazol-4-yl)-2-[2-(2,2,2-trifluoroethylamino)-4-pyridinyl]-1,3-oxazole-4-carboxamide;hydrochloride	1175586: Inhibition of IRAK4 (unknown origin)	ic50	0.0002	uM
5-[[(1R,2S)-2-aminocyclohexyl]amino]-N-[3-(difluoromethyl)-1-methylpyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1234028: Inhibition of human IRAK4 assessed as phosphorylation of fluorescent peptide substrate after 30 mins by fluorescent polarization reader	ic50	0.0002	uM
2-[[(1R,2S)-2-aminocyclohexyl]amino]-N-[3-(difluoromethyl)-1-methylpyrazol-4-yl]thieno[2,3-b]pyrazine-7-carboxamide	1255381: Inhibition of IRAK4 (unknown origin)	ic50	0.0002	uM
5-[[(3R)-azepan-3-yl]amino]-N-[3-(difluoromethyl)-1-methylpyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1255381: Inhibition of IRAK4 (unknown origin)	ic50	0.0002	uM
5-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy]-3-methoxynaphthalene-2-carboxamide	1534899: Inhibition of IRAK4 (unknown origin)	ic50	0.0002	uM
N-[2-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-6-morpholin-4-yl-1-oxo-3H-isoindol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1547741: Inhibition of IRAK4 in human whole blood assessed as inhibition of R848-induced IL-6 production preincubated for 90 mins followed by R848 stimulation and measured after 3.5 hrs by MSD assay	ic50	0.0002	uM
N-[2-(3-hydroxy-3-methylbutyl)-6-morpholin-4-yl-1-oxo-3H-isoindol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1547741: Inhibition of IRAK4 in human whole blood assessed as inhibition of R848-induced IL-6 production preincubated for 90 mins followed by R848 stimulation and measured after 3.5 hrs by MSD assay	ic50	0.0002	uM
6-(difluoromethyl)-N-[2-(oxan-4-yl)-7-propan-2-yloxyimidazo[1,2-a]pyridin-6-yl]pyridine-2-carboxamide	2081400: Inhibition of IRAK4 (unknown origin) using biotinylated peptide (IRAK1 activation loop sequence 360-389) as substrate incubated for 2 hrs in presence of 1 mM ATP by mesoscale detection method	ic50	0.0002	uM
6-(difluoromethyl)-N-[7-ethoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)imidazo[1,2-a]pyridin-6-yl]pyridine-2-carboxamide	2081400: Inhibition of IRAK4 (unknown origin) using biotinylated peptide (IRAK1 activation loop sequence 360-389) as substrate incubated for 2 hrs in presence of 1 mM ATP by mesoscale detection method	ic50	0.0002	uM
N-[6-(difluoromethyl)-2-pyridinyl]-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-7-propan-2-yloxyimidazo[1,2-a]pyridine-6-carboxamide	2081400: Inhibition of IRAK4 (unknown origin) using biotinylated peptide (IRAK1 activation loop sequence 360-389) as substrate incubated for 2 hrs in presence of 1 mM ATP by mesoscale detection method	ic50	0.0002	uM
2-[4-[acetyl(methyl)amino]cyclohexyl]-N-imidazo[1,2-b]pyridazin-3-yl-6-methoxyindazole-5-carboxamide	1886982: Inhibition of recombinant human full-length His-tagged IRAK4 expressed in baculovirus infected insect cells using KKARFSRFAGSSPSQSSMVAR as substrate preincubated for 15 mins followed by substrate addition and measured after 2 hrs by LC-MS/MS analysis	ic50	0.0002	uM
N-imidazo[1,2-b]pyridazin-3-yl-6-methoxy-2-(2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)indazole-5-carboxamide	1886982: Inhibition of recombinant human full-length His-tagged IRAK4 expressed in baculovirus infected insect cells using KKARFSRFAGSSPSQSSMVAR as substrate preincubated for 15 mins followed by substrate addition and measured after 2 hrs by LC-MS/MS analysis	ic50	0.0002	uM
N-[1-[(1S,2R)-2-fluorocyclopropyl]-2-oxo-3-pyridinyl]-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-6-propan-2-yloxyindazole-5-carboxamide	2144571: Inhibition of IRAK4 (unknown origin) incubated for 1 hr in presence of ATP by Mesoscale assay	ic50	0.0002	uM
N-(1-cyclopropyl-2-oxo-3-pyridinyl)-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-7-propan-2-yloxyimidazo[1,2-a]pyrimidine-6-carboxamide	2071096: Inhibition of human IRAK4 using biotinylated peptide substrate incubated for 3 hrs by microplate reader assay	ic50	0.0002	uM
N-[1-[(1S,2R)-2-fluorocyclopropyl]-2-oxo-3-pyridinyl]-2-[(1S,4R)-1-(methoxymethyl)-2-oxabicyclo[2.2.1]heptan-4-yl]-7-propan-2-yloxyimidazo[1,2-a]pyrimidine-6-carboxamide	2071096: Inhibition of human IRAK4 using biotinylated peptide substrate incubated for 3 hrs by microplate reader assay	ic50	0.0002	uM
N-[1-[(1S,2R)-2-fluorocyclopropyl]-2-oxo-3-pyridinyl]-2-[(1S,4R)-1-methyl-2-oxabicyclo[2.2.1]heptan-4-yl]-7-propan-2-yloxyimidazo[1,2-a]pyrimidine-6-carboxamide	2071096: Inhibition of human IRAK4 using biotinylated peptide substrate incubated for 3 hrs by microplate reader assay	ic50	0.0002	uM
N-(1-cyclopropyl-2-oxo-3-pyridinyl)-2-[(1S,4R)-1-(methoxymethyl)-2-oxabicyclo[2.2.1]heptan-4-yl]-7-propan-2-yloxyimidazo[1,2-a]pyrimidine-6-carboxamide	2071096: Inhibition of human IRAK4 using biotinylated peptide substrate incubated for 3 hrs by microplate reader assay	ic50	0.0002	uM
N-[1-[(1S,2R)-2-fluorocyclopropyl]-2-oxo-3-pyridinyl]-2-(2-oxabicyclo[2.1.1]hexan-4-yl)-7-propan-2-yloxyimidazo[1,2-a]pyrimidine-6-carboxamide	2071096: Inhibition of human IRAK4 using biotinylated peptide substrate incubated for 3 hrs by microplate reader assay	ic50	0.0002	uM
N-[1-[(1S,2R)-2-fluorocyclopropyl]-2-oxo-3-pyridinyl]-2-[1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl]-7-propan-2-yloxyimidazo[1,2-a]pyrimidine-6-carboxamide	2071096: Inhibition of human IRAK4 using biotinylated peptide substrate incubated for 3 hrs by microplate reader assay	ic50	0.0002	uM
N-[1-[(1S,2R)-2-fluorocyclopropyl]-2-oxo-3-pyridinyl]-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-7-propan-2-yloxyimidazo[1,2-a]pyrimidine-6-carboxamide	2071096: Inhibition of human IRAK4 using biotinylated peptide substrate incubated for 3 hrs by microplate reader assay	ic50	0.0002	uM
N-(6-fluoropyrazolo[1,5-a]pyrimidin-3-yl)-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-7-propan-2-yloxyimidazo[1,2-a]pyrimidine-6-carboxamide	2081400: Inhibition of IRAK4 (unknown origin) using biotinylated peptide (IRAK1 activation loop sequence 360-389) as substrate incubated for 2 hrs in presence of 1 mM ATP by mesoscale detection method	ic50	0.0002	uM
2-[4-[[(2R)-2-hydroxypropanoyl]-methylamino]cyclohexyl]-N-imidazo[1,2-b]pyridazin-3-yl-6-methoxyindazole-5-carboxamide	1886982: Inhibition of recombinant human full-length His-tagged IRAK4 expressed in baculovirus infected insect cells using KKARFSRFAGSSPSQSSMVAR as substrate preincubated for 15 mins followed by substrate addition and measured after 2 hrs by LC-MS/MS analysis	ic50	0.0002	uM
N-[1-[(1S,2R)-2-methylcyclopropyl]-2-oxo-3-pyridinyl]-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-6-propan-2-yloxypyrazolo[3,4-b]pyridine-5-carboxamide	2144571: Inhibition of IRAK4 (unknown origin) incubated for 1 hr in presence of ATP by Mesoscale assay	ic50	0.0002	uM
N-[1-[(1S,2R)-2-fluorocyclobutyl]-2-oxo-3-pyridinyl]-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-7-propan-2-yloxyimidazo[1,2-a]pyrimidine-6-carboxamide	2071096: Inhibition of human IRAK4 using biotinylated peptide substrate incubated for 3 hrs by microplate reader assay	ic50	0.0002	uM
N-[2-[4-[[3-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]oxy]propyl-methylamino]methyl]cyclohexyl]-6-(2-hydroxypropan-2-yl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide	2085323: Binding affinity to CRBN/IRAK4 in human OCI-Ly10 cells assessed as dissociation constant by DiscoverX Kd Elect assay	kd	0.0002	uM
N-[5-(2,2-dimethylpropanoylamino)-1-[4-(hydroxymethyl)cyclohexyl]benzimidazol-2-yl]-3-(trifluoromethyl)benzamide	1262276: Inhibition of recombinant full length IRAK-4 (unknown origin) using the biotinylated substrate RRRVTSPARRS by chemiluminescent ELISA	ki	0.0003	uM
1-[[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy]-7-methoxyisoquinoline-6-carboxamide	1448131: Inhibition of N-terminal His6-tagged human full length IRAK4 preincubated for 20 mins followed by biotinylated-AGAGRDKYKTLRQIR substrate addition in presence of ATP measured after 60 mins by DELFIA method	ic50	0.0003	uM
(1R,2S,5R)-3-[[5-(1,3-benzothiazol-2-yl)-2-[(2,6-dimethyl-4-pyridinyl)amino]pyrimidin-4-yl]amino]-5-(hydroxymethyl)cyclopentane-1,2-diol;hydrochloride	1175595: Inhibition of IRAK4 (unknown origin) by fluorescence polarization based kinase assay	ic50	0.0003	uM
N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide	2085395: Binding affinity to IRAK4 (unknown origin) assessed as dissociation constant	kd	0.0003	uM
5-[[(1R,2S)-2-aminocyclohexyl]amino]-N-(3-carbamoyl-1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide	1234028: Inhibition of human IRAK4 assessed as phosphorylation of fluorescent peptide substrate after 30 mins by fluorescent polarization reader	ic50	0.0003	uM
5-[[(1R,2S)-2-aminocyclohexyl]amino]-N-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1234028: Inhibition of human IRAK4 assessed as phosphorylation of fluorescent peptide substrate after 30 mins by fluorescent polarization reader	ic50	0.0003	uM
2-[[(1R,2S)-2-aminocyclohexyl]amino]-N-(3-chloro-1-methylpyrazol-4-yl)thieno[2,3-b]pyrazine-7-carboxamide	1255381: Inhibition of IRAK4 (unknown origin)	ic50	0.0003	uM
N-[2-(3-methoxy-3-methylbutyl)-6-morpholin-4-yl-1-oxo-3H-isoindol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1547741: Inhibition of IRAK4 in human whole blood assessed as inhibition of R848-induced IL-6 production preincubated for 90 mins followed by R848 stimulation and measured after 3.5 hrs by MSD assay	ic50	0.0003	uM
N-[6-(difluoromethyl)-2-pyridinyl]-2-(oxan-4-yl)-7-propan-2-yloxyimidazo[1,2-a]pyridine-6-carboxamide	2081400: Inhibition of IRAK4 (unknown origin) using biotinylated peptide (IRAK1 activation loop sequence 360-389) as substrate incubated for 2 hrs in presence of 1 mM ATP by mesoscale detection method	ic50	0.0003	uM
4-[3-[2-[2-[3-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-3-oxopropoxy]ethoxy]ethoxy]prop-1-ynyl]-7-methoxy-1-[[(2S)-5-oxopyrrolidin-2-yl]methoxy]isoquinoline-6-carboxamide	1564077: Binding affinity to human IRK4 using myelin basic protein as substrate by [gamma-33P]-ATP assay	ic50	0.0003	uM
N-(1-cyclopropyl-2-oxo-3-pyridinyl)-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-6-propan-2-yloxyindazole-5-carboxamide	2144571: Inhibition of IRAK4 (unknown origin) incubated for 1 hr in presence of ATP by Mesoscale assay	ic50	0.0003	uM
N-(1-cyclopropyl-2-oxo-3-pyridinyl)-2-[(1S,4R)-1-methyl-2-oxabicyclo[2.2.1]heptan-4-yl]-7-propan-2-yloxyimidazo[1,2-a]pyrimidine-6-carboxamide	2071096: Inhibition of human IRAK4 using biotinylated peptide substrate incubated for 3 hrs by microplate reader assay	ic50	0.0003	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Silicon Dioxide	decreases expression	2
Cyclosporine	increases expression	2
Protein Kinase Inhibitors	decreases activity, affects binding, decreases reaction, increases reaction, increases expression (+2 more)	2
takinib	decreases activity	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
glycidyl methacrylate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
nickel chloride	increases expression	1
perfluorooctanoic acid	increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
casticin	increases expression	1
liquiritigenin	affects reaction, increases reaction, increases phosphorylation, decreases expression, decreases reaction (+2 more)	1
acanthoic acid	affects cotreatment, decreases reaction, increases expression, increases reaction	1
entinostat	increases expression	1
resiquimod	increases expression, increases phosphorylation, affects binding, decreases activity, decreases reaction (+1 more)	1
lipopolysaccharide, Helicobacter pylori	increases expression, increases reaction	1
abrine	decreases expression	1
mono-isobutyl phthalate	decreases methylation, increases abundance	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Air Pollutants	increases abundance, increases expression, affects cotreatment	1
Ethanol	affects cotreatment, decreases reaction, increases expression, increases reaction	1
Allergens	affects cotreatment, increases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	affects cotreatment, increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Fusaric Acid	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases reaction, increases expression	1

ChEMBL screening assays

799 unique, capped per target: 795 binding, 3 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1012695	Binding	Inhibition of IRAK4 at 5 uM	Synthesis and evaluation of novel inhibitors of Pim-1 and Pim-2 protein kinases. — J Med Chem
CHEMBL1963808	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: IRAK4	PubChem BioAssay data set
CHEMBL4325217	ADMET	Inhibition of human IRAK4 at 1 uM relative to control	Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis. — J Med Chem

Cellosaurus cell lines

10 cell lines: 9 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8IN	Abcam HCT 116 IRAK4 KO	Cancer cell line	Male
CVCL_B8XI	Abcam MCF-7 IRAK4 KO	Cancer cell line	Female
CVCL_B9KY	Abcam A-549 IRAK4 KO	Cancer cell line	Male
CVCL_D7SG	Ubigene A-549 IRAK4 KO	Cancer cell line	Male
CVCL_D8NC	Ubigene HCT 116 IRAK4 KO	Cancer cell line	Male
CVCL_D9HE	Ubigene HEK293 IRAK4 KO	Transformed cell line	Female
CVCL_E0FB	Ubigene HeLa IRAK4 KO	Cancer cell line	Female
CVCL_E1LB	HyCyte HL-60 KO-hIRAK4	Cancer cell line	Female
CVCL_E1N1	HyCyte THP-1 KO-hIRAK4	Cancer cell line	Male
CVCL_SS87	HAP1 IRAK4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03815357	Not specified	COMPLETED	What is the Incidence of an Immune Disorder in Children With Invasive Pneumococcal Disease (IPD)?
NCT07471516	PHASE1/PHASE2	RECRUITING	Zoledronic Acid Treatment in Patients With Congenital Dyserythropoietic Anemia
NCT02964494	Not specified	RECRUITING	The Congenital Dyserythropoietic Anemia Registry (CDAR)
NCT03983629	Not specified	UNKNOWN	Registry of Congenital Dyserythropoietic Anemia
NCT06213402	Not specified	RECRUITING	RADeep Multicenter European Epidemiological Platform for Patients Diagnosed With Rare Anemia Disorders (RADs)
NCT07206095	Not specified	RECRUITING	Integrative Diagnosis for SCD and Other RADs