IRAK1

Summary

IRAK1 (interleukin 1 receptor associated kinase 1, HGNC:6112) is a protein-coding gene on chromosome Xq28, encoding Interleukin-1 receptor-associated kinase 1 (P51617). Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens.

This gene encodes the interleukin-1 receptor-associated kinase 1, one of two putative serine/threonine kinases that become associated with the interleukin-1 receptor (IL1R) upon stimulation. This gene is partially responsible for IL1-induced upregulation of the transcription factor NF-kappa B. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3654 — RefSeq curated summary.

At a glance

• Gene–disease (curated): systemic lupus erythematosus (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 14
• Clinical variants (ClinVar): 193 total — 11 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 80
• Druggable target: yes — 50 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_001569

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6112
Approved symbol	IRAK1
Name	interleukin 1 receptor associated kinase 1
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	IRAK, pelle
Ensembl gene	ENSG00000184216
Ensembl biotype	protein_coding
OMIM	300283
Entrez	3654

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 24 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000369973, ENST00000369974, ENST00000369980, ENST00000393687, ENST00000429936, ENST00000437278, ENST00000443220, ENST00000444230, ENST00000444254, ENST00000455690, ENST00000463031, ENST00000467236, ENST00000477274, ENST00000699980, ENST00000927318, ENST00000927319, ENST00000927320, ENST00000927321, ENST00000927322, ENST00000927323, ENST00000927324, ENST00000927325, ENST00000944206, ENST00000944207, ENST00000944208, ENST00000944209, ENST00000944210, ENST00000944211, ENST00000944212

RefSeq mRNA: 4 — MANE Select: NM_001569 NM_001025242, NM_001025243, NM_001410701, NM_001569

CCDS: CCDS14740, CCDS35443, CCDS35444, CCDS94700

Canonical transcript exons

ENST00000369980 — 14 exons

Exon	Start	End
ENSE00001294478	154019431	154019598
ENSE00001309390	154018975	154019078
ENSE00001316581	154019197	154019328
ENSE00001329751	154018599	154018787
ENSE00001896763	154019677	154019902
ENSE00001927643	154010507	154011917
ENSE00003464582	154016949	154017067
ENSE00003473357	154012529	154012678
ENSE00003473617	154018006	154018120
ENSE00003488926	154016437	154016644
ENSE00003510632	154016032	154016097
ENSE00003614815	154014042	154014278
ENSE00003630544	154018291	154018355
ENSE00003789611	154013043	154013433

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.9535 / max 292.0406, expressed in 1820 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200948	50.0846	1820
200947	0.4436	264
200945	0.4253	186

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	99.47	gold quality
pancreatic ductal cell	CL:0002079	99.19	silver quality
cervix squamous epithelium	UBERON:0006922	98.26	silver quality
endothelial cell	CL:0000115	97.82	gold quality
gingival epithelium	UBERON:0001949	97.34	gold quality
tongue squamous epithelium	UBERON:0006919	97.13	gold quality
gingiva	UBERON:0001828	96.75	gold quality
squamous epithelium	UBERON:0006914	96.03	gold quality
periodontal ligament	UBERON:0008266	95.80	gold quality
lower esophagus mucosa	UBERON:0035834	95.35	gold quality
duodenum	UBERON:0002114	94.91	gold quality
stromal cell of endometrium	CL:0002255	94.84	gold quality
ileal mucosa	UBERON:0000331	94.84	gold quality
epithelium of esophagus	UBERON:0001976	94.84	gold quality
endometrium epithelium	UBERON:0004811	94.84	gold quality
esophagus squamous epithelium	UBERON:0006920	94.74	gold quality
granulocyte	CL:0000094	94.64	gold quality
nephron tubule	UBERON:0001231	94.61	gold quality
superior surface of tongue	UBERON:0007371	94.46	gold quality
vermiform appendix	UBERON:0001154	94.40	gold quality
epithelial cell of pancreas	CL:0000083	94.39	silver quality
gastrocnemius	UBERON:0001388	94.29	gold quality
bone marrow cell	CL:0002092	94.26	gold quality
body of pancreas	UBERON:0001150	94.25	gold quality
spleen	UBERON:0002106	94.21	gold quality
esophagus mucosa	UBERON:0002469	94.13	gold quality
cervix epithelium	UBERON:0004801	94.06	silver quality
pylorus	UBERON:0001166	93.89	gold quality
visceral pleura	UBERON:0002401	93.88	gold quality
amniotic fluid	UBERON:0000173	93.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPD, IRF6, NFKB, RARA, YY1

miRNA regulators (miRDB)

39 targeting IRAK1, 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-5193	100.00	67.26	1744
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-589-5P	98.72	66.96	927
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-7850-5P	98.12	67.28	1111
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-617	96.79	65.96	738
HSA-MIR-6760-3P	96.35	68.31	1001
HSA-MIR-591	96.29	68.16	611

Literature-anchored findings (GeneRIF, showing 40)

• proximal signaling molecules involved in LPS-induced NF-kappa B activation have a requisite involvement in LPS-induced apoptosis and that the pathways leading to NF-kappa B activation and apoptosis diverge downstream of IRAK-1. (PMID:11777917)
• Gram-negative flagellin-induced self-tolerance is associated with a block in interleukin-1 receptor-associated kinase release from toll-like receptor 5. (PMID:11953430)
• Down-regulation of the common Toll-like receptor intracellular signaling factor IRAK in vitro will lead to a state of cross-tolerance and decreased IL-1 beta and TNF-alpha production upon subsequent challenge with multiple microbial toxins. (PMID:12055225)
• Identification of threonine 66 as a functionally critical residue of the protein (PMID:12138165)
• In lipopolysaccharide (LPS)-tolerant monocytes IRAK-1 is not activated in response to LPS restimulation, although protein and mRNA levels remain normal or slightly up-regulated. (PMID:12391239)
• association of a haplotype (196Phe/532Ser) in the interleukin-1-receptor-associated kinase (IRAK1) gene with low radial bone mineral density in two independent populations (PMID:12619925)
• phosphorylates Stat1 on serine 727 in response to interleukin-1 and affects gene expression (PMID:12856330)
• Pellino2 interacts with kinase-active as well as kinase-inactive IRAK1 and IRAK4 (PMID:12860405)
• IRAK-1 is the central kinase involved in the activation of the macrophage at distant sites during septic shock (PMID:14752294)
• Involvement of CD14/TLR4, CR3, and phosphatidylinositol 3-kinase in the degradation of IL-1 receptor-associated kinase in response to LPS. (PMID:15069085)
• IRAK1 is essential for lipopolysaccharide-induced interleukin-10 gene expression (PMID:15465816)
• study shows that PBMCs of patients with advanced gastric cancer show poor production of TNF and IL-12p40 in response to stimulation with tumor cells in vitro & this unresponsiveness is associated in some patients with diminished IRAK-1 expression in vivo (PMID:15523691)
• the Hsp90.Cdc37 molecular chaperone module has a central role in interleukin-1 receptor-associated-kinase-dependent signaling by toll-like receptors (PMID:15647277)
• Only LPS, not taxol, caused a dramatic decrease in IRAK1 protein levels. (PMID:15829295)
• Presence of a regulated, alternative splice variant of IRAK1 that functions as a kinase-dead, dominant-negative protein adds further complexity to the variety of mechanisms that regulate Toll/IL-1 receptor signaling and subsequent inflammatory response. (PMID:16024789)
• following stimulation by exogenous CD26, Tollip and IRAK-1 dissociate from caveolin-1, and IRAK-1 is then phosphorylated in the cytosol, leading to the upregulation of CD86 via activation of NF-kappaB (PMID:16107720)
• Monarch-1 associates with IRAK-1 but not MyD88, resulting in the blockage of IRAK-1 hyperphosphorylation (PMID:16203735)
• The critical IRAK1 role in LMP1-induced NF-kappaB activation is in mediating p65/RelA S536 phosphorylation through an effect on p38 or other p65 S536 kinases. (PMID:16477006)
• Data show that IRAK-1 acts as the essential upstream adaptor that recruits BCL10 to the TLR4 signaling complex and mediates signaling to NF-kappaB through the BCL10-MALT1-TRAF6-TAK1 cascade. (PMID:16831874)
• ozLDL inhibited NF-kappaB and IRAK-1-associated signaling which may impair immune function and promote apoptosis (PMID:17053167)
• Death domain of IRAK-1 is a multimerization domain which mediates association towards MyD88, Tollip, Irak-4 & Irak-1. (PMID:17276401)
• variation in the IRAK1 gene is associated with C-reactive protein concentration in Caucasian women in the Diabetes Heart Study (PMID:17382928)
• 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)
• Variant IRAK-1 is associated with alterations in multiple intracellular events that are likely to contribute to increased NF-kappa B activation and inflammatory responses in individuals with this commonly occurring IRAK-1 variant haplotype. (PMID:17785851)
• IRAK-2 plays a more central role than IRAK-1 in TLR signaling to NFkappaB through TRAF6 ubiquitination (PMID:17878161)
• MyD88, IRAK1 and TRAF6 proteins are crucial early mediators for the IL-1-induced MMP-13 regulation through MAPK pathways and AP-1 activity. (PMID:17905570)
• Constitutive association of MyD88 with IRAK1 was observed in all three of HTLV-I-transformed T cells, but not in HTLV-I-negative T cells (PMID:17920759)
• 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)
• SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of systemic lupus erythematosus. (PMID:18050247)
• TRAF6 is involved but with different mechanisms of IRAK-1-induced activation of NF-kappaB. (PMID:18070982)
• 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)
• Both cytosolic and nuclear actions of IRAK-1 participate in the activation of NF-kappaB-dependent transcriptional events. (PMID:18276832)
• The sites of IRAK-1 ubiquitination were mapped to Lys134 and Lys180, and arginine substitution of these residues impaired IL-1R/TLR-mediated IRAK-1 ubiquitination. (PMID:18347055)
• signals from the IL-1 receptor segregate into at least two separate pathways at the level of IRAK1; one couples through TRAF6 to NFkappaB activation while a second utilizes a TRAF6-independent pathway that is responsible for mRNA stabilization (PMID:18411265)
• Significant & strong 2- & 3-locus interactions between SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) & IRAK1 (rs1059703)were associated with the response to whole-cell vaccine pertussis vaccination in 490 1-yr-old children. (PMID:18987746)
• TLR-ligands can render DCs tolerant with respect to TNF gene expression by a mechanism that likely involves blockade of signal transduction at the level of IRAK-1. (PMID:19025640)
• Leishmania can exploit a host protein tyrosine phosphatase, namely SHP-1, to directly inactivate IRAK-1. (PMID:19104650)
• Interleukin-1 Receptor-Associated Kinase is held in a closed, inactive conformation via an intramolecular mechanism involving its C-terminal domain and possibly the death domain. (PMID:19166926)
• Over-expression of interleukin-1 receptor-associated kinase-1 led to increased constitutive and cytokine induced production of Chemokines, CC. (PMID:19166933)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	irak1	ENSDARG00000025949
mus_musculus	Irak1	ENSMUSG00000031392
rattus_norvegicus	Irak1	ENSRNOG00000060869
drosophila_melanogaster	pll	FBGN0010441
drosophila_melanogaster	Haspin	FBGN0046706
caenorhabditis_elegans		WBGENE00004029
caenorhabditis_elegans	hasp-1	WBGENE00007258
caenorhabditis_elegans		WBGENE00012159
caenorhabditis_elegans	hasp-2	WBGENE00021214

Paralogs (4): IRAK3 (ENSG00000090376), IRAK2 (ENSG00000134070), HASPIN (ENSG00000177602), IRAK4 (ENSG00000198001)

Protein

Protein identifiers

Interleukin-1 receptor-associated kinase 1 — P51617 (reviewed: P51617)

All UniProt accessions (8): D3YTB5, P51617, F8WAB6, H7C1F0, H7C224, H7C2I6, H7C3C1, H7C3G8

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. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. 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 the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.

Subunit / interactions. Homodimer. Forms a complex with TRAF6, PELI1, IRAK4 and MYD88. Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. The TRAF6-PELI1-IRAK4-MYD88 complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Interaction with MYD88 recruits IRAK1 to the stimulated receptor complex. Interacts with TOLLIP; this interaction occurs in the cytosol prior to receptor activation. Interacts with IL1RL1. Interacts with PELI1 and TRAF6. Interacts (when polyubiquitinated) with IKBKG/NEMO. Interacts with RSAD2/viperin. Interacts with IRAK1BP1. Interacts with PELI2. Interacts with ZC3H12A; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB. Interacts with IRAK4. Interacts with PELI3. Interacts with INAVA; the interaction takes place upon PRR stimulation. Interacts (via C-terminus) with NFATC4 (via N-terminus). (Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation. (Microbial infection) Interacts with alphaviruses SINV, CHIKV, RRV, VEEV and EEEV capsid proteins; the interactions lead to inhibition of IRAK1-dependent signaling.

Subcellular location. Cytoplasm. Nucleus. Lipid droplet.

Tissue specificity. Isoform 1 and isoform 2 are ubiquitously expressed in all tissues examined, with isoform 1 being more strongly expressed than isoform 2.

Post-translational modifications. Following recruitment on the activated receptor complex, phosphorylated on Thr-209, probably by IRAK4, resulting in a conformational change of the kinase domain, allowing further phosphorylations to take place. Thr-387 phosphorylation in the activation loop is required to achieve full enzymatic activity. Polyubiquitinated by TRAF6 after cell stimulation with IL-1-beta by PELI1, PELI2 and PELI3. Polyubiquitination occurs with polyubiquitin chains linked through ‘Lys-63’. Ubiquitination promotes interaction with NEMO/IKBKG. Also sumoylated; leading to nuclear translocation.

Domain organisation. The ProST region is composed of many proline and serine residues (more than 20 of each) and some threonines. This region is the site of IRAK-1 hyperphosphorylation.

Miscellaneous. Inactive.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P51617-1	1, a	yes
P51617-2	2, b
P51617-3	3
P51617-4	4

RefSeq proteins (4): NP_001020413, NP_001020414, NP_001397630, NP_001560* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR035533	Death_IRAK1	Domain

Pfam: PF00069, PF00531

Enzyme classification (BRENDA):

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
POLY(GLU4-TYR)	0.018–0.659	10
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
EEEEY	—	0

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 (75 total): helix 16, strand 12, sequence variant 11, modified residue 7, compositionally biased region 5, region of interest 5, binding site 4, splice variant 4, mutagenesis site 4, domain 2, cross-link 2, chain 1, active site 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6BFN	X-RAY DIFFRACTION	2.26

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51617-F1	70.27	0.41

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): 340 (proton acceptor)

Ligand- & substrate-binding residues (4): 218–226; 239; 342–345; 358

Post-translational modifications (9): 66, 131, 209, 371, 375, 387, 556, 134, 180

Mutagenesis-validated functional residues (4):

Position	Phenotype
209	completely abolishes auto-phosphorylation in the kinase domain.
239	loss of kinase activity.
340	loss of kinase activity.
387	loss of kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

53 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-209543	p75NTR recruits signalling complexes
R-HSA-209560	NF-kB is activated and signals survival
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-450302	activated TAK1 mediates p38 MAPK activation
R-HSA-450321	JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8986944	Transcriptional Regulation by MECP2
R-HSA-9020702	Interleukin-1 signaling
R-HSA-937039	IRAK1 recruits IKK complex
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
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-975144	IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation
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-166166	MyD88-independent TLR4 cascade
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) 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

MSigDB gene sets: 492 (showing top): AP1_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, WWTAAGGC_UNKNOWN, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, REACTOME_NOD1_2_SIGNALING_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, PAL_PRMT5_TARGETS_UP, GOBP_TOLL_LIKE_RECEPTOR_9_SIGNALING_PATHWAY, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS

GO Biological Process (36): regulation of cytokine-mediated signaling pathway (GO:0001959), toll-like receptor signaling pathway (GO:0002224), MyD88-dependent toll-like receptor signaling pathway (GO:0002755), regulation of DNA-templated transcription (GO:0006355), canonical NF-kappaB signal transduction (GO:0007249), JNK cascade (GO:0007254), Toll signaling pathway (GO:0008063), lipopolysaccharide-mediated signaling pathway (GO:0031663), positive regulation of type I interferon production (GO:0032481), response to lipopolysaccharide (GO:0032496), toll-like receptor 2 signaling pathway (GO:0034134), toll-like receptor 4 signaling pathway (GO:0034142), toll-like receptor 9 signaling pathway (GO:0034162), cellular response to heat (GO:0034605), intracellular signal transduction (GO:0035556), interleukin-33-mediated signaling pathway (GO:0038172), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), innate immune response (GO:0045087), protein autophosphorylation (GO:0046777), positive regulation of smooth muscle cell proliferation (GO:0048661), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), type I interferon-mediated signaling pathway (GO:0060337), interleukin-1-mediated signaling pathway (GO:0070498), response to interleukin-1 (GO:0070555), cellular response to hypoxia (GO:0071456), positive regulation of leukocyte adhesion to vascular endothelial cell (GO:1904996), immune system process (GO:0002376), protein phosphorylation (GO:0006468), signal transduction (GO:0007165), positive regulation of macromolecule metabolic process (GO:0010604), cytokine-mediated signaling pathway (GO:0019221), response to other organism (GO:0051707), cellular response to lipopolysaccharide (GO:0071222), cellular response to cytokine stimulus (GO:0071345), positive regulation of intracellular signal transduction (GO:1902533)

GO Molecular Function (13): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), kinase activity (GO:0016301), protein kinase binding (GO:0019901), heat shock protein binding (GO:0031072), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), lipid droplet (GO:0005811), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), endosome membrane (GO:0010008), protein-containing complex (GO:0032991), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-23 pathways:

Category	Pathways
p75NTR signals via NF-kB	2
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	2
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	2
MyD88 cascade initiated on plasma membrane	2
MAP kinase activation	2
MyD88 dependent cascade initiated on endosome	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
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Toll Like Receptor 3 (TLR3) Cascade	1
Interleukin-1 signaling	1
TRIF (TICAM1)-mediated TLR4 signaling	1
Negative regulation of the PI3K/AKT network	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytokine-mediated signaling pathway	2
cell surface receptor signaling pathway	2
cell surface toll-like receptor signaling pathway	2
intracellular anatomical structure	2
canonical NF-kappaB signal transduction	2
regulation of canonical NF-kappaB signal transduction	2
protein kinase activity	2
protein binding	2
protein dimerization activity	2
regulation of signal transduction	1
regulation of response to cytokine stimulus	1
pattern recognition receptor signaling pathway	1
toll-like receptor signaling pathway	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
intracellular signaling cassette	1
MAPK cascade	1
cellular response to lipopolysaccharide	1
positive regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
endolysosomal toll-like receptor signaling pathway	1
response to heat	1
cellular response to stress	1
signal transduction	1
positive regulation of intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
immune response	1
defense response to symbiont	1
protein phosphorylation	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

3688 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRAK1	MYD88	P78397	999
IRAK1	TRAF6	Q9Y4K3	999
IRAK1	TLR4	O00206	998
IRAK1	TIRAP	P58753	997
IRAK1	IL1R1	P14778	996
IRAK1	TOLLIP	Q9H0E2	994
IRAK1	TRAF3	Q13114	994
IRAK1	IRAK4	Q9NWZ3	988
IRAK1	IRAK2	O43187	987
IRAK1	IRAK3	Q9Y616	984
IRAK1	CHUK	O15111	983
IRAK1	PELI1	Q96FA3	982
IRAK1	IRF7	Q92985	979
IRAK1	IL1B	P01584	978
IRAK1	TAB2	Q9NYJ8	972

IntAct

161 interactions, top by confidence:

A	B	Type	Score
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
GET4	GET3	psi-mi:“MI:0914”(association)	0.800
TRAF6	IRAK1	psi-mi:“MI:0915”(physical association)	0.770
IRAK1	TRAF6	psi-mi:“MI:0915”(physical association)	0.770
IRAK1	PELI2	psi-mi:“MI:0915”(physical association)	0.740
PELI2	IRAK1	psi-mi:“MI:0915”(physical association)	0.740
PELI1	IRAK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.730
PELI1	IRAK1	psi-mi:“MI:0914”(association)	0.730
PELI1	IRAK1	psi-mi:“MI:0915”(physical association)	0.730
MYD88	IRAK1	psi-mi:“MI:0915”(physical association)	0.720
IRAK1	MYD88	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
IRAK4	IRAK2	psi-mi:“MI:0914”(association)	0.710
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
IRAK1	PIN1	psi-mi:“MI:0915”(physical association)	0.650
PIN1	IRAK1	psi-mi:“MI:0407”(direct interaction)	0.650
PIN1	IRAK1	psi-mi:“MI:0915”(physical association)	0.650

BioGRID (533): IRAK1 (Affinity Capture-RNA), IRAK1 (Affinity Capture-Western), IRAK1 (Affinity Capture-Western), IRAK1 (Affinity Capture-Western), IRAK1 (Affinity Capture-MS), IRAK1 (Biochemical Activity), IRAK1 (Reconstituted Complex), IRAK1 (Reconstituted Complex), AIFM1 (Affinity Capture-MS), ATP1A1 (Affinity Capture-MS), ATP5B (Affinity Capture-MS), BAG2 (Affinity Capture-MS), CALU (Affinity Capture-MS), CCT2 (Affinity Capture-MS), CCT3 (Affinity Capture-MS)

ESM2 similar proteins: A0JNJ4, A2AKB4, A2APT9, A5PJC7, B1ASB6, O94761, O94989, P51617, P60924, Q14154, Q32LQ1, Q3TYX8, Q3U381, Q494U1, Q4KLY2, Q5F267, Q5FWH6, Q5R866, Q5RA50, Q5RA67, Q5SXM2, Q5SYB0, Q5T7N3, Q5VTJ3, Q6PCP7, Q6ZMQ8, Q6ZMY3, Q6ZUX3, Q6ZVH7, Q7Z3H0, Q80VJ8, Q80YE4, Q86V42, Q8BG26, Q8BG80, Q8BWA8, Q8BZW2, Q8C886, Q8IW93, Q8IY92

Diamond homologs: C0LGD7, C0LGE0, C0LGG4, C0LGG7, C0LGG9, C0LGH3, C0LGU1, C0LGU5, F4J0D2, F4JEQ2, G5ECP4, O22187, O22476, O48814, O49839, O49840, O64556, O65468, O65530, O80939, P43293, P46573, P51617, Q05652, Q06548, Q0WRY5, Q0WVM4, Q1PE89, Q1RMT8, Q2R560, Q39191, Q5XF79, Q62406, Q65XV8, Q69JN6, Q6ZCZ2, Q7F8Q9, Q7G768, Q7XV05, Q8GUQ5

SIGNOR signaling

44 interactions.

A	Effect	B	Mechanism
IRAK1	up-regulates	PELI3	phosphorylation
IRAK4	“up-regulates activity”	IRAK1	phosphorylation
IL1R1	“up-regulates activity”	IRAK1
IRAK1	“up-regulates activity”	IRAK1	phosphorylation
IRAK1	up-regulates	STAT3	phosphorylation
PELI1	“up-regulates quantity by expression”	IRAK1	ubiquitination
PELI2	up-regulates	IRAK1	ubiquitination
PELI3	up-regulates	IRAK1	ubiquitination
AKT	“down-regulates activity”	IRAK1	phosphorylation
TOLLIP	“down-regulates activity”	IRAK1	binding
TRAF6	“up-regulates activity”	IRAK1	ubiquitination
AKT1	“down-regulates activity”	IRAK1	phosphorylation
IRAK1	“up-regulates activity”	GLIPR2	phosphorylation
IL1RL1	“up-regulates activity”	IRAK1	binding
IRAK1	“up-regulates activity”	IRF7	phosphorylation
IRAK1	“up-regulates activity”	PELI2	phosphorylation
hsa-mir-146a-5p	“down-regulates quantity by repression”	IRAK1	“post transcriptional regulation”
MYD88	“up-regulates activity”	IRAK1	binding
IRAK1	“up-regulates activity”	TRAF6	binding
SOCS1	down-regulates	IRAK1	binding
IRAK1	“up-regulates activity”	PELI1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 143 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
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	6	56.4×	6e-08
TRAF6-mediated induction of TAK1 complex within TLR4 complex	6	52.9×	8e-08
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	6	38.5×	5e-07
activated TAK1 mediates p38 MAPK activation	6	36.8×	5e-07
Interleukin-1 family signaling	7	23.5×	8e-07
NOD1/2 Signaling Pathway	6	23.5×	7e-06
TAK1-dependent IKK and NF-kappa-B activation	6	22.3×	8e-06
Interleukin-1 signaling	13	19.9×	4e-11

GO biological processes:

GO term	Partners	Fold	FDR
MyD88-dependent toll-like receptor signaling pathway	7	57.0×	2e-08
interleukin-1-mediated signaling pathway	6	41.9×	2e-06
lipopolysaccharide-mediated signaling pathway	6	27.5×	1e-05
toll-like receptor 4 signaling pathway	6	27.5×	1e-05
positive regulation of JNK cascade	6	8.5×	5e-03
positive regulation of canonical NF-kappaB signal transduction	13	8.2×	2e-06

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — PCM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	1
Uncertain significance	63
Likely benign	20
Benign	9

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1526878	GRCh37/hg19 Xq28(chrX:153261390-153322230)	Pathogenic
1526879	GRCh37/hg19 Xq28(chrX:153269534-153438781)	Pathogenic
1526880	GRCh37/hg19 Xq28(chrX:153277379-153317880)	Pathogenic
155659	GRCh38/hg38 Xq28(chrX:154004083-154055920)x1	Pathogenic
2425261	NC_000023.10:g.(?153279389)(153296228_?)del	Pathogenic
2580294	GRCh37/hg19 Xq28(chrX:153217915-153618382)x2	Pathogenic
3062477	GRCh37/hg19 Xq28(chrX:153261202-153421839)	Pathogenic
3245037	NC_000023.10:g.(?153277310)(153298028_?)del	Pathogenic
394095	GRCh37/hg19 Xq28(chrX:152886474-153368990)x2	Pathogenic
441760	GRCh37/hg19 Xq28(chrX:153253477-153438781)x3	Pathogenic
833488	NC_000023.10:g.(?152954010)(153363142_?)dup	Pathogenic
807888	GRCh37/hg19 Xq28(chrX:153281481-153296901)x1	Likely pathogenic

SpliceAI

2176 predictions. Top by Δscore:

Variant	Effect	Δscore
X:154016435:ACCAC:A	donor_gain	1.0000
X:154016436:CCACC:C	donor_gain	1.0000
X:154016476:T:TA	donor_gain	1.0000
X:154016477:C:A	donor_gain	1.0000
X:154016493:C:CA	donor_gain	1.0000
X:154016640:TGGAA:T	acceptor_gain	1.0000
X:154016641:GGAA:G	acceptor_gain	1.0000
X:154016642:GAA:G	acceptor_gain	1.0000
X:154016643:AA:A	acceptor_gain	1.0000
X:154016644:AC:A	acceptor_loss	1.0000
X:154016645:C:CC	acceptor_gain	1.0000
X:154016646:T:C	acceptor_gain	1.0000
X:154016646:T:TC	acceptor_gain	1.0000
X:154016943:CCTCA:C	donor_loss	1.0000
X:154016944:CTCAC:C	donor_loss	1.0000
X:154016945:TCA:T	donor_loss	1.0000
X:154016946:CA:C	donor_loss	1.0000
X:154016947:ACC:A	donor_loss	1.0000
X:154016948:CCT:C	donor_gain	1.0000
X:154017068:C:CC	acceptor_gain	1.0000
X:154018000:GCCTA:G	donor_loss	1.0000
X:154018001:CCTA:C	donor_loss	1.0000
X:154018002:CTAC:C	donor_loss	1.0000
X:154018003:TA:T	donor_loss	1.0000
X:154018004:A:AC	donor_gain	1.0000
X:154018004:ACCTG:A	donor_loss	1.0000
X:154018005:C:A	donor_loss	1.0000
X:154018005:C:CC	donor_gain	1.0000
X:154018005:CCTGG:C	donor_gain	1.0000
X:154018116:GAAAC:G	acceptor_gain	1.0000

AlphaMissense

4570 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:154018611:C:A	K239N	0.999
X:154018611:C:G	K239N	0.999
X:154019460:A:G	L92P	0.999
X:154019475:A:G	L87P	0.999
X:154019475:A:T	L87H	0.999
X:154019487:A:G	L83P	0.999
X:154019679:A:G	F45S	0.999
X:154019687:C:A	W42C	0.999
X:154019687:C:G	W42C	0.999
X:154019689:A:G	W42R	0.999
X:154019689:A:T	W42R	0.999
X:154018659:A:C	F223L	0.998
X:154018659:A:T	F223L	0.998
X:154018661:A:G	F223L	0.998
X:154019439:A:T	I99N	0.998
X:154019487:A:T	L83H	0.998
X:154019598:G:T	A46D	0.998
X:154019678:G:C	F45L	0.998
X:154019678:G:T	F45L	0.998
X:154019679:A:C	F45C	0.998
X:154019680:A:G	F45L	0.998
X:154019724:A:G	F30S	0.998
X:154016599:G:C	D358E	0.997
X:154016599:G:T	D358E	0.997
X:154016644:A:C	S343R	0.997
X:154016644:A:T	S343R	0.997
X:154016950:T:G	S343R	0.997
X:154016951:C:A	K342N	0.997
X:154016951:C:G	K342N	0.997
X:154016953:T:C	K342E	0.997

dbSNP variants (sampled 300 via entrez): RS1000137506 (X:154011199 T>G), RS1000252339 (X:154011398 C>T), RS1002802175 (X:154013700 G>A), RS1004364911 (X:154015734 G>A), RS1005276589 (X:154020892 C>G,T), RS1005616683 (X:154020460 C>T), RS1006041039 (X:154013998 G>A,C), RS1006093510 (X:154013748 G>A), RS1006833792 (X:154017660 G>A), RS1006937111 (X:154010245 G>A), RS1007128870 (X:154010574 T>C,G), RS1008505785 (X:154016234 G>A,C), RS1009442746 (X:154016247 G>A), RS1010227449 (X:154018191 G>A,C), RS1010340225 (X:154010598 C>A,T)

Disease associations

OMIM: gene MIM:300283 | disease phenotypes: MIM:300673, MIM:300260

GenCC curated gene-disease

Disease	Classification	Inheritance
systemic lupus erythematosus	Supportive	Unknown
immunodeficiency disease	Limited	X-linked

Mondo (5): cleft palate (MONDO:0016064), severe neonatal-onset encephalopathy with microcephaly (MONDO:0010397), syndromic X-linked intellectual disability Lubs type (MONDO:0010283), systemic lupus erythematosus (MONDO:0007915), immunodeficiency disease (MONDO:0021094)

Orphanet (3): Cleft palate (Orphanet:2014), MECP2-related severe neonatal encephalopathy (Orphanet:209370), Proximal Xq28 duplication syndrome (Orphanet:1762)

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000079	Abnormality of the urinary system
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000100	Nephrotic syndrome
HP:0000123	Nephritis
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000707	Abnormality of the nervous system
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000951	Abnormality of the skin
HP:0000969	Edema
HP:0000988	Skin rash
HP:0000992	Cutaneous photosensitivity
HP:0001250	Seizure
HP:0001324	Muscle weakness
HP:0001369	Arthritis
HP:0001541	Ascites
HP:0001596	Alopecia
HP:0001698	Pericardial effusion
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001888	Decreased total lymphocyte count
HP:0001937	Microangiopathic hemolytic anemia
HP:0001945	Fever
HP:0002013	Vomiting

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002318_151	Rheumatoid arthritis	3.000000e-12
GCST002318_181	Rheumatoid arthritis	5.000000e-16
GCST003155_27	Systemic lupus erythematosus	2.000000e-15
GCST003252_4	Systemic lupus erythematosus	8.000000e-14
GCST003599_17	Systemic lupus erythematosus	4.000000e-10
GCST004867_3	Systemic lupus erythematosus	8.000000e-07
GCST005523_40	Celiac disease	3.000000e-08
GCST005568_10	Rheumatoid arthritis (ACPA-positive)	1.000000e-12
GCST005569_32	Rheumatoid arthritis	3.000000e-12
GCST011389_5	Rheumatoid arthritis	5.000000e-10
GCST011956_124	Systemic lupus erythematosus	6.000000e-54
GCST90002388_279	Lymphocyte count	3.000000e-09
GCST90002389_497	Lymphocyte percentage of white cells	6.000000e-22
GCST90002399_110	Neutrophil percentage of white cells	4.000000e-23

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590
C566878	Encephalopathy, Neonatal Severe, Due To Mecp2 Mutations (supp.)
C537723	Lubs X-linked mental retardation syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3357 (SINGLE PROTEIN), CHEMBL4742279 (PROTEIN-PROTEIN INTERACTION), CHEMBL4748228 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

50 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 360,385 (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
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL180022	NERATINIB	4	9,404
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2105712	AFATINIB DIMALEATE	4	3,215
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301607	FILGOTINIB	4	2,905
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL3301612	ENCORAFENIB	4	4,624
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL939	GEFITINIB	4
CHEMBL941	IMATINIB	4
CHEMBL2105728	CRENOLANIB	3
CHEMBL223360	LINIFANIB	3
CHEMBL31965	CANERTINIB	3
CHEMBL428690	ALVOCIDIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL124660	TANDUTINIB	2
CHEMBL1721885	SU-014813	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 (6 total), top 6:

Ligand	Action	Affinity	Parameter
belizatinib	Inhibition	8.24	pKd
compound 1 [WO2012007375]	Inhibition	7.26	pIC50
IRAK-1/4 inhibitor	Inhibition	6.52	pIC50
Takinib	Inhibition	6.41	pIC50
compound 7 [WO2012007375]	Inhibition	6.01	pIC50
nacresertib	Inhibition	5.39	pIC50

Binding affinities (BindingDB)

253 measured of 423 human assays (423 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[2-[4-(aminomethyl)piperidin-1-yl]-5-chlorophenyl]-6-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	55 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[7-(4-hydroxycyclohexyl)oxyquinolin-6-yl]thieno[3,2-d]pyrimidine-7-carboxamide	IC50	70 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
cis-(1S,3R)-3-acetamido-N-[4-(4-fluoro-2-methoxyphenyl)-2-pyridinyl]cyclohexane-1-carboxamide	IC50	94 nM	US-9067888: Inhibitors of protein kinases
N-[7-(4-hydroxycyclohexyl)oxyquinolin-6-yl]thieno[3,2-d]pyrimidine-7-carboxamide	IC50	123 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[5-chloro-2-(4-hydroxycyclohexyl)oxyphenyl]thieno[3,2-d]pyrimidine-7-carboxamide	IC50	126 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[5-chloro-2-(4-hydroxycyclohexyl)oxyphenyl]-6-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	163 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[7-(4-hydroxycyclohexyl)oxyquinolin-6-yl]thieno[3,2-d]pyrimidine-7-carboxamide	IC50	168 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
6-hydroxy-N-(7-methoxyquinolin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	200 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[2-(2-hydroxyethylamino)-7-methoxyquinolin-6-yl]thieno[3,2-d]pyrimidine-7-carboxamide	IC50	200 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[7-[(1R,3R)-3-hydroxycyclopentyl]oxyquinolin-6-yl]thieno[3,2-d]pyrimidine-7-carboxamide	IC50	246 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
2-[2-hydroxyethyl(methyl)amino]-N-(7-methoxyquinolin-6-yl)thieno[3,2-d]pyrimidine-7-carboxamide	IC50	300 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[5-chloro-2-[4-[(dimethylamino)methyl]piperidin-1-yl]phenyl]-6-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	307 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[7-(4-hydroxy-2-methylbutan-2-yl)oxyquinolin-6-yl]thieno[3,2-d]pyrimidine-7-carboxamide	IC50	364 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[2-[4-(aminomethyl)piperidin-1-yl]-4-(phenylcarbamoyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	450 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[2-[4-(aminomethyl)piperidin-1-yl]-5-chlorophenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	IC50	463 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
N-[7-(3-aminopropoxy)quinolin-6-yl]thieno[3,2-d]pyrimidine-7-carboxamide	IC50	529 nM	US-9255110: Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
5-methoxy-8,15,17,25,29-pentazahexacyclo[23.3.1.12,6.119,23.08,16.09,14]hentriaconta-1(29),2(31),3,5,9,11,13,15,19,21,23(30),27-dodecaene-18,26-dione	IC50	550 nM	US-10064861: Macrocyclic pyridazinone derivatives
3,31-dimethyl-4,5,8,15,17,25,29-heptazahexacyclo[23.3.1.12,5.119,23.08,16.09,14]hentriaconta-1(29),2(31),3,9,11,13,15,19,21,23(30),27-undecaene-18,26-dione	IC50	550 nM	US-10064861: Macrocyclic pyridazinone derivatives
2,2-Dimethyl-propionic acid 2-[3-(6-oxo-3-pyridin-3-yl-6H-pyridazin-1-ylmethyl)-benzoylamino]-1H-benzoimidazol-5-yl ester	IC50	550 nM	US-9567320: Pyridazinone-amides derivatives
N-(1H-Benzoimidazol-2-yl)-3-(6-oxo-3-pyrimidin-5-yl-6H-pyridazin-1-ylmethyl)-benzamide	IC50	550 nM	US-9567320: Pyridazinone-amides derivatives
N-(1H-benzo[d]imidazol-2-yl)-3-(2-cyano-5-(pyridin-3-yl)phenoxy)benzamide	IC50	550 nM	US-9567320: Pyridazinone-amides derivatives
N-(1H-benzo[d]imidazol-2-yl)-3-((3-(6-methylpyridazin-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)benzamide	IC50	550 nM	US-9567320: Pyridazinone-amides derivatives
N-(5,6-dimethoxy-1H-benzo[d]imidazol-2-yl)-3-((6-oxo-3-(pyridin-3-yl)pyridazin-1(6H)-yl)methyl)benzamide	IC50	550 nM	US-9567320: Pyridazinone-amides derivatives
12-methyl-21-oxa-1,9,12,13,16,26-hexazatetracyclo[20.3.1.13,7.010,14]heptacosa-3(27),4,6,10,13,22(26),23-heptaene-8,15,25-trione	IC50	550 nM	US-9624246: Pyridazinone macrocycles as IRAK inhibitors and uses thereof
5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]-N-(piperidin-4-ylmethyl)pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
5-(1-methylpyrazol-3-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]-N-(piperidin-3-ylmethyl)pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]-N-(oxan-4-ylmethyl)pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
2-[3-(1-methylpyrazol-4-yl)phenyl]-5-(5-methyl-1,3,4-thiadiazol-2-yl)-N-propan-2-ylpyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
[(3R)-3-hydroxypyrrolidin-1-yl]-[5-[2-[3-(1-methylpyrazol-4-yl)phenyl]-4-(propan-2-ylamino)pyrimidin-5-yl]-1,3,4-thiadiazol-2-yl]methanone	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
[(3R)-3-hydroxypyrrolidin-1-yl]-[5-[2-[3-(1-methylpyrazol-4-yl)phenyl]-4-(piperidin-3-ylamino)pyrimidin-5-yl]-1,3,4-thiadiazol-2-yl]methanone	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
[(3S)-3-hydroxypyrrolidin-1-yl]-[5-[6-[6-(1-methylpyrazol-4-yl)-2-pyridinyl]-4-(propan-2-ylamino)-3-pyridinyl]-1,3,4-thiadiazol-2-yl]methanone	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
N-cyclopropyl-5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
N-cyclobutyl-5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
N-cyclopentyl-5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
3-[[5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]propan-1-ol	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]-N-(oxolan-3-yl)pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
N-[(3,3-difluorocyclobutyl)methyl]-5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
N-[(1-methylcyclobutyl)methyl]-5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
4-N-[5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-yl]cyclohexane-1,4-diamine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
3-[[5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]cyclobutan-1-ol	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
N-(3,3-difluorocyclobutyl)-5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]-N-(3-methylsulfonylcyclobutyl)pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
N-(3-fluorocyclobutyl)-5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
3-[[[5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]methyl]oxetan-3-ol	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
[1-[[[5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]methyl]cyclobutyl]methanol	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
(2S)-3-[[5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]propane-1,2-diol	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
N-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl]-5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
N-[2-[[5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-yl]amino]ethyl]acetamide	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]-N-(oxetan-3-ylmethyl)pyrimidin-4-amine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof
2-N-[5-(1-methylpyrazol-4-yl)-2-[3-(1-methylpyrazol-4-yl)phenyl]pyrimidin-4-yl]spiro[3.3]heptane-2,6-diamine	IC50	550 nM	US-9790221: Heteroaryl compounds as IRAK inhibitors and uses thereof

ChEMBL bioactivities

727 potent at pChembl≥5 of 736 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.28	Kd	0.53	nM	CHEMBL6078253
9.00	IC50	1	nM	CHEMBL6077980
8.70	IC50	2	nM	CHEMBL5283628
8.59	Kd	2.6	nM	CHEMBL6083120
8.54	Kd	2.9	nM	CHEMBL5927784
8.46	Kd	3.5	nM	CHEMBL6002371
8.42	Kd	3.8	nM	CHEMBL6077980
8.40	IC50	4	nM	CHEMBL6168382
8.30	IC50	5	nM	CHEMBL6078253
8.27	IC50	5.34	nM	CHEMBL5949720
8.25	Kd	5.6	nM	CHEMBL2172315
8.24	Kd	5.7	nM	CHEMBL2172308
8.22	IC50	6	nM	CHEMBL6083120
8.22	IC50	6	nM	CHEMBL6171386
8.21	Kd	6.1	nM	LESTAURTINIB
8.15	IC50	7	nM	CHEMBL5907315
8.15	IC50	7	nM	CHEMBL6171790
8.05	IC50	9	nM	CHEMBL4568087
8.05	IC50	9	nM	CHEMBL4782804
8.05	IC50	9	nM	CHEMBL256713
8.05	IC50	9	nM	CHEMBL5991427
8.05	IC50	9	nM	CHEMBL6168158
8.01	Kd	9.7	nM	R-406
8.00	IC50	10	nM	CHEMBL6176830
8.00	IC50	10	nM	CHEMBL6176725
8.00	IC50	10	nM	CHEMBL6174213
8.00	Ki	10	nM	R-406
8.00	Ki	10	nM	CENISERTIB
7.96	IC50	11	nM	CHEMBL6164800
7.92	Ki	12	nM	CHEMBL3736465
7.92	IC50	12	nM	CHEMBL6162952
7.92	IC50	12	nM	CHEMBL6173599
7.90	Ki	12.59	nM	CHEMBL1994241
7.90	Ki	12.59	nM	CHEMBL2000345
7.89	Kd	13	nM	CHEMBL5633185
7.85	IC50	14	nM	CHEMBL3735401
7.85	IC50	14.2	nM	CHEMBL3393607
7.85	IC50	14	nM	CHEMBL6176513
7.85	Kd	14	nM	SUNITINIB
7.82	IC50	15	nM	CHEMBL3746678
7.82	IC50	15	nM	CHEMBL6078490
7.82	IC50	15	nM	CHEMBL6162578
7.80	IC50	16	nM	STAUROSPORINE
7.80	IC50	16	nM	CHEMBL6175302
7.80	Ki	15.85	nM	CHEMBL1969301
7.75	Ki	18	nM	CHEMBL3735673
7.75	IC50	18	nM	CHEMBL6102868
7.75	IC50	18	nM	CHEMBL6165599
7.72	IC50	19	nM	CHEMBL4550702
7.72	IC50	19	nM	CHEMBL6091831

PubChem BioAssay actives

139 with measured affinity, of 1103 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
4-(1-methylcyclopropyl)oxy-N-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-6-pyrimidin-5-ylpyrido[3,2-d]pyrimidin-2-amine	1943102: Inhibition of IRAK1 (unknown origin) in presence of 25 uM ATP	ic50	0.0020	uM
3,5-difluoro-N-[6-[[4-(2-hydroxypropan-2-yl)piperidin-1-yl]methyl]-1-[4-(propan-2-ylcarbamoyl)cyclohexyl]benzimidazol-2-yl]benzamide	703118: Binding affinity to human IRAK1 by Ambit titration assay	kd	0.0056	uM
4-fluoro-N-[6-[[4-(2-hydroxypropan-2-yl)piperidin-1-yl]methyl]-1-[4-(propan-2-ylcarbamoyl)cyclohexyl]benzimidazol-2-yl]benzamide	703118: Binding affinity to human IRAK1 by Ambit titration assay	kd	0.0057	uM
(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-one	507569: Binding affinity to IRAK1	kd	0.0061	uM
N-[4-[[3-(prop-2-enoylamino)benzoyl]amino]phenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1725918: Inhibition of recombinant IRAK1 (unknown origin) by Invitrogen adapta assay	ic50	0.0090	uM
N-(2-methoxy-4-morpholin-4-ylphenyl)-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1725920: Inhibition of wild-type human partial length IRAK1 (R194 to S712 residues) expressed in mammalian expression system by Kinomescan method	ic50	0.0090	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637088: Inhibition of recombinant human GST-tagged IRAK1 (194 to 712 residues) catalytic domain expressed in baculovirus expression system by Adapta assay	ic50	0.0090	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624837: Binding constant for IRAK1 kinase domain	kd	0.0097	uM
4-[6-[4-(2-piperidin-1-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637088: Inhibition of recombinant human GST-tagged IRAK1 (194 to 712 residues) catalytic domain expressed in baculovirus expression system by Adapta assay	ic50	0.0100	uM
N-[1-[4-(2-hydroxyethyl)phenyl]-5-(piperidin-1-ylmethyl)benzimidazol-2-yl]-3-(trifluoromethyl)benzamide	1262277: Inhibition of IRAK-1 (unknown origin)	ki	0.0120	uM
6-(3-hydroxycyclobutyl)oxy-2,2-dimethyl-N-[6-(1-methylpyrazol-4-yl)-2-pyridinyl]-3H-furo[2,3-b]pyridine-5-carboxamide	2135995: Binding affinity to IRAK1 (unknown origin) by kinomescan competition binding assay	kd	0.0130	uM
2-[4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-5H-benzo[b]carbazol-8-yl)pyrazol-1-yl]-N,N-dimethylacetamide	1267027: Inhibition of IRAK1 (unknown origin)	ic50	0.0140	uM
Sunitinib	507569: Binding affinity to IRAK1	kd	0.0140	uM
3-[[(E)-4-(dimethylamino)but-2-enoyl]amino]-N-[4-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide	1725920: Inhibition of wild-type human partial length IRAK1 (R194 to S712 residues) expressed in mammalian expression system by Kinomescan method	ic50	0.0142	uM
8-[1-[3-(dimethylamino)propyl]pyrazol-4-yl]-9-ethyl-6,6-dimethyl-11-oxo-5H-benzo[b]carbazole-3-carbonitrile	1267027: Inhibition of IRAK1 (unknown origin)	ic50	0.0150	uM
(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-one	1715314: Inhibition of human IRAK1 using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0160	uM
N-[1-(4-hydroxycyclohexyl)-5-(piperidin-1-ylmethyl)benzimidazol-2-yl]-3-nitrobenzamide	1262277: Inhibition of IRAK-1 (unknown origin)	ki	0.0180	uM
4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637088: Inhibition of recombinant human GST-tagged IRAK1 (194 to 712 residues) catalytic domain expressed in baculovirus expression system by Adapta assay	ic50	0.0190	uM
1-[4-[4-[(5-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethanone	1419876: Inhibition of recombinant human N-terminal His6-tagged IRAK1 (194 to end residues) expressed in baculovirus infected Sf21 insect cells in presence of 25 uM ATP	ic50	0.0210	uM
6-[7-methoxy-6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]-N-pyrrolidin-3-ylpyridin-2-amine	1894583: Inhibition of IRAK1 (unknown origin)	ic50	0.0226	uM
N-(4-morpholin-4-ylcyclohexyl)-5-(oxan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine	1471967: Inhibition of recombinant N-terminal His6-tagged human IRAK1 (194 end residues) expressed in baculovirus infected Sf21 cells	ic50	0.0230	uM
N-[5-[4-(hydroxymethyl)piperidin-1-yl]-2-morpholin-4-yl-1,3-benzothiazol-6-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1562122: Inhibition of human recombinant full length N-terminal His6-tagged IRAK1 (Argl94 to Ser712 residues) expressed in insect cells using H-KKARFSRFAGSSPSQSSMVAR as substrate incubated for 60 mins by fluorescence polarisation assay	ki	0.0240	uM
N-[3-[[3-(prop-2-enoylamino)benzoyl]amino]phenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1725918: Inhibition of recombinant IRAK1 (unknown origin) by Invitrogen adapta assay	ic50	0.0250	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	624837: Binding constant for IRAK1 kinase domain	kd	0.0260	uM
methyl 4-[4-[[6-(cyanomethyl)-2-[(1-methylpyrazol-4-yl)amino]pyrido[3,2-d]pyrimidin-4-yl]amino]cyclohexyl]piperazine-1-carboxylate	1526936: Inhibition of IRAK1 (unknown origin)	ic50	0.0270	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148601: Binding affinity to human IRAK1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0293	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2168211: Inhibition of human wild type IRAK1 using RB-CTF as substrate preincubated for 2 hrs followed by ATP addition and measured every 2 mins for 2.5 hrs by spectrophotometric analysis	ic50	0.0390	uM
Pacritinib	1921554: Inhibition of IRAK-1 (unknown origin)	ic50	0.0395	uM
methyl 4-[4-[(6-cyanoquinazolin-4-yl)amino]cyclohexyl]piperazine-1-carboxylate	1526936: Inhibition of IRAK1 (unknown origin)	ic50	0.0440	uM
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-diamine	624837: Binding constant for IRAK1 kinase domain	kd	0.0450	uM
N-[4-[[4-(prop-2-enoylamino)benzoyl]amino]phenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1725918: Inhibition of recombinant IRAK1 (unknown origin) by Invitrogen adapta assay	ic50	0.0470	uM
N-[1-[4-(hydroxymethyl)cyclohexyl]-5-(piperidin-1-ylmethyl)benzimidazol-2-yl]-3-nitrobenzamide	1262277: Inhibition of IRAK-1 (unknown origin)	ki	0.0480	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624837: Binding constant for IRAK1 kinase domain	kd	0.0480	uM
Crizotinib	624837: Binding constant for IRAK1 kinase domain	kd	0.0490	uM
N-[4-[[3-[[(E)-4-(dimethylamino)but-2-enoyl]amino]benzoyl]amino]phenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1725918: Inhibition of recombinant IRAK1 (unknown origin) by Invitrogen adapta assay	ic50	0.0520	uM
N-[3-[[4-(prop-2-enoylamino)benzoyl]amino]phenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1725918: Inhibition of recombinant IRAK1 (unknown origin) by Invitrogen adapta assay	ic50	0.0550	uM
N-[2-[4-(aminomethyl)piperidin-1-yl]-5-chlorophenyl]-6-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxamide	1175609: Inhibition of IRAK1 (unknown origin)	ic50	0.0550	uM
N-[4-[4-[2-[[(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]-2-oxoethoxy]piperidin-1-yl]-2-methoxyphenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1807245: Inhibition of truncated human N-terminal GST-fusion tagged IRAK1 (194 to 712 residues) expressed in baculovirus expression system using FAM-labelled peptide as substrate preincubated for 10 mins followed by substrate addition and further incubated for 1 hr in presence of ATP at Km concentration by caliper mobility shift assay	ic50	0.0600	uM
5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-[4-(methylsulfonylmethyl)-2-pyridinyl]pyridin-2-amine	1814980: Inhibition of IRAK1 (unknown origin) assessed as dissociation constant by DiscoveryX assay	kd	0.0610	uM
3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-(1H-indol-7-ylamino)-1,2,4-triazine-6-carboxamide	1199665: Competitive binding affinity to human IRAK1	kd	0.0670	uM
Gefitinib	624837: Binding constant for IRAK1 kinase domain	kd	0.0690	uM
N-[4-[[3-[[(E)-4-[methyl-[3-[2-[2-[2-[2-[6-(5-methyl-2-oxoimidazolidin-4-yl)hexanoylamino]ethoxy]ethoxy]ethoxy]ethylamino]-3-oxopropyl]amino]but-2-enoyl]amino]benzoyl]amino]phenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1725918: Inhibition of recombinant IRAK1 (unknown origin) by Invitrogen adapta assay	ic50	0.0700	uM
N-[1-[4-(hydroxymethyl)cyclohexyl]-5-(piperidin-1-ylmethyl)benzimidazol-2-yl]-3-(trifluoromethyl)benzamide	1262277: Inhibition of IRAK-1 (unknown origin)	ki	0.0720	uM
1-[4-[4-[[5-(oxan-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]cyclohexyl]piperazin-1-yl]ethanone	1419876: Inhibition of recombinant human N-terminal His6-tagged IRAK1 (194 to end residues) expressed in baculovirus infected Sf21 insect cells in presence of 25 uM ATP	ic50	0.0720	uM
N-[4-[4-[2-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-2-oxoethoxy]piperidin-1-yl]-2-methoxyphenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1807245: Inhibition of truncated human N-terminal GST-fusion tagged IRAK1 (194 to 712 residues) expressed in baculovirus expression system using FAM-labelled peptide as substrate preincubated for 10 mins followed by substrate addition and further incubated for 1 hr in presence of ATP at Km concentration by caliper mobility shift assay	ic50	0.0720	uM
N-[4-[4-[2-[[(2S)-1-[(2S,4S)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-2-oxoethoxy]piperidin-1-yl]-2-methoxyphenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1807245: Inhibition of truncated human N-terminal GST-fusion tagged IRAK1 (194 to 712 residues) expressed in baculovirus expression system using FAM-labelled peptide as substrate preincubated for 10 mins followed by substrate addition and further incubated for 1 hr in presence of ATP at Km concentration by caliper mobility shift assay	ic50	0.0790	uM
N-[4-[4-[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-oxopropyl]piperazin-1-yl]-2-methoxyphenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide	1807245: Inhibition of truncated human N-terminal GST-fusion tagged IRAK1 (194 to 712 residues) expressed in baculovirus expression system using FAM-labelled peptide as substrate preincubated for 10 mins followed by substrate addition and further incubated for 1 hr in presence of ATP at Km concentration by caliper mobility shift assay	ic50	0.0800	uM
N-[2-(dimethylamino)-5-[4-(hydroxymethyl)piperidin-1-yl]-1,3-benzothiazol-6-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide	1562122: Inhibition of human recombinant full length N-terminal His6-tagged IRAK1 (Argl94 to Ser712 residues) expressed in insect cells using H-KKARFSRFAGSSPSQSSMVAR as substrate incubated for 60 mins by fluorescence polarisation assay	ki	0.0950	uM
4,5,8,15,17,25,29-heptazahexacyclo[23.3.1.12,5.119,23.08,16.09,14]hentriaconta-1(29),2(31),3,9,11,13,15,19,21,23(30),27-undecaene-18,26-dione	1175604: Inhibition of IRAK1 (unknown origin) by radiochemical assay	ic50	0.1000	uM
5-hydroxy-8,15,17,25,29-pentazahexacyclo[23.3.1.12,6.119,23.08,16.09,14]hentriaconta-1(29),2(31),3,5,9,11,13,15,19,21,23(30),27-dodecaene-18,26-dione	1175604: Inhibition of IRAK1 (unknown origin) by radiochemical assay	ic50	0.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	5
bisphenol A	affects expression, affects cotreatment, increases methylation, increases expression	4
sodium arsenite	increases abundance, increases expression	2
cobaltous chloride	decreases expression	2
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	increases abundance, increases expression, affects expression	2
Atrazine	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation, affects expression	2
Fluorouracil	increases expression, affects response to substance	2
Lipopolysaccharides	decreases reaction, increases ubiquitination, increases degradation, increases phosphorylation	2
Plant Extracts	decreases reaction, increases expression	2
takinib	decreases activity	1
2-anisidine	decreases expression	1
tylophorine	increases expression	1
triphenyl phosphate	affects expression	1
propylparaben	increases expression	1
kaempferol	decreases reaction, increases ubiquitination	1
lead acetate	increases expression	1
titanium dioxide	increases expression	1
beta-lapachone	decreases expression	1
tetrabromobisphenol A	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
potassium chromate(VI)	decreases expression	1
cupric chloride	increases expression	1
zinc sulfide	affects cotreatment, increases expression	1
hydroquinone	decreases expression	1
beta-methylcholine	affects expression	1
cadmium selenide	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1

ChEMBL screening assays

363 unique, capped per target: 361 binding, 1 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1037171	Binding	Inhibition of IRAK1 at 10 uM	Structure-activity relationship studies of chalcone leading to 3-hydroxy-4,3’,4’,5’-tetramethoxychalcone and its analogues as potent nuclear factor kappaB inhibitors and their anticancer activities. — J Med Chem
CHEMBL1963802	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: IRAK1	PubChem BioAssay data set
CHEMBL4359941	ADMET	Inhibition of human recombinant full length N-terminal His6-tagged IRAK1 (Argl94 to Ser712 residues) expressed in insect cells using H-KKARFSRFAGSSPSQSSMVAR as substrate incubated for 60 mins by fluorescence polarisation assay	Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors. — J Med Chem

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8IM	Abcam HCT 116 IRAK1 KO	Cancer cell line	Male
CVCL_B9KX	Abcam A-549 IRAK1 KO	Cancer cell line	Male
CVCL_D2FX	Abcam MCF-7 IRAK1 KO	Cancer cell line	Female
CVCL_D7SF	Ubigene A-549 IRAK1 KO	Cancer cell line	Male
CVCL_D9HD	Ubigene HEK293 IRAK1 KO	Transformed cell line	Female
CVCL_SS83	HAP1 IRAK1 (-) 1	Cancer cell line	Male
CVCL_SS84	HAP1 IRAK1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients