ITK

Summary

ITK (IL2 inducible T cell kinase, HGNC:6171) is a protein-coding gene on chromosome 5q33.3, encoding Tyrosine-protein kinase ITK/TSK (Q08881). Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.

This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein contains both SH2 and SH3 domains which are often found in intracellular kinases. It is thought to play a role in T-cell proliferation and differentiation.

Source: NCBI Gene 3702 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lymphoproliferative syndrome 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 622 total — 16 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes — 39 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005546

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6171
Approved symbol	ITK
Name	IL2 inducible T cell kinase
Location	5q33.3
Locus type	gene with protein product
Status	Approved
Aliases	EMT, PSCTK2, LYK
Ensembl gene	ENSG00000113263
Ensembl biotype	protein_coding
OMIM	186973
Entrez	3702

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 5 protein_coding, 5 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000422843, ENST00000517779, ENST00000519402, ENST00000519749, ENST00000519759, ENST00000520173, ENST00000520555, ENST00000521769, ENST00000522616, ENST00000523926, ENST00000696962, ENST00000862614, ENST00000862615, ENST00000862616

RefSeq mRNA: 1 — MANE Select: NM_005546 NM_005546

CCDS: CCDS4336

Canonical transcript exons

ENST00000422843 — 17 exons

Exon	Start	End
ENSE00002205312	157240062	157240195
ENSE00003490214	157232340	157232394
ENSE00003522900	157214191	157214319
ENSE00003529076	157208889	157208993
ENSE00003584380	157222863	157223014
ENSE00003600533	157228296	157228361
ENSE00003607467	157238109	157238191
ENSE00003650904	157217867	157217907
ENSE00003663291	157211287	157211368
ENSE00003969056	157241646	157241720
ENSE00003969057	157245726	157245790
ENSE00003969058	157252607	157255185
ENSE00003969059	157244262	157244478
ENSE00003969060	157180840	157181115
ENSE00003969061	157245881	157245999
ENSE00003969062	157243623	157243794
ENSE00003969063	157248850	157249007

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 94.43.

FANTOM5 (CAGE): breadth broad, TPM avg 20.2275 / max 1504.9457, expressed in 570 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59793	19.2315	283
59791	0.7323	365
59792	0.1109	63
59795	0.0833	36
59796	0.0695	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	94.43	gold quality
thymus	UBERON:0002370	93.67	gold quality
blood	UBERON:0000178	91.08	gold quality
lymph node	UBERON:0000029	90.71	gold quality
vermiform appendix	UBERON:0001154	89.53	gold quality
spleen	UBERON:0002106	83.70	gold quality
colonic epithelium	UBERON:0000397	83.37	gold quality
bone marrow cell	CL:0002092	83.04	gold quality
bone marrow	UBERON:0002371	82.41	gold quality
caecum	UBERON:0001153	80.72	gold quality
superficial temporal artery	UBERON:0001614	80.20	gold quality
gall bladder	UBERON:0002110	78.74	gold quality
small intestine Peyer’s patch	UBERON:0003454	78.09	gold quality
epithelium of nasopharynx	UBERON:0001951	78.06	gold quality
ileal mucosa	UBERON:0000331	77.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.19	gold quality
tonsil	UBERON:0002372	76.65	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.58	gold quality
small intestine	UBERON:0002108	75.31	gold quality
upper lobe of left lung	UBERON:0008952	74.93	gold quality
upper lobe of lung	UBERON:0008948	74.11	gold quality
jejunal mucosa	UBERON:0000399	73.85	gold quality
right lung	UBERON:0002167	73.00	gold quality
omental fat pad	UBERON:0010414	72.61	gold quality
peritoneum	UBERON:0002358	72.53	gold quality
adipose tissue of abdominal region	UBERON:0007808	72.30	gold quality
lung	UBERON:0002048	71.87	gold quality
mucosa of transverse colon	UBERON:0004991	71.42	gold quality
rectum	UBERON:0001052	71.02	gold quality
left uterine tube	UBERON:0001303	69.63	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	22.30
E-CURD-112	yes	4.23
E-CURD-89	no	1092.06
E-MTAB-7606	no	912.37
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, FOXQ1, HNF4A, MBD2, MYB, NR4A3

miRNA regulators (miRDB)

133 targeting ITK, 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-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• REPO plays a key role in both glial development and diversification. (PMID:12702656)
• Gcm acts synergistically with other factors to control repo transcription in glial cells (PMID:15939231)
• novel role for the dVDUP1 tumor suppressor during nervous system development as a regulatory target for REPO during gliogenesis (PMID:18262515)
• These results indicate that cas could be directly suppressed by Repo. (PMID:19635453)
• we characterized three cis-regulatory elements (PMID:22051777)
• REPO directly regulates DRPR expression. gcm and repo have a critical role in controlling glial phagocytic function through regulation of SIMU and DRPR specific expression. (PMID:25046770)
• Repo expression inhibits the expression of hemocyte-specific genes in the nervous system (PMID:30504274)
• Repo expression is continuously required in adult glia to transcriptionally regulate the highly conserved function of neurotransmitter recycling in both males and females. (PMID:31064860)
• Studies of Itk deletion mutants indicate that the amino acids in the N-terminal 152 residues and proline-rich domains enhance catalysis by affecting turnover rate rather than by substrate binding. (PMID:11437596)
• Itk catalytic activity is inhibited by the peptidyl prolyl isomerase activity of cyclophilin A (CypA). (PMID:11830645)
• In this review, the pathways are discussed by which Itk might impact the differentiation of T helper (Th) cells. (PMID:16931156)
• Itk forms dimers in the membrane and that receptors that recruit Itk do so to specific membrane regions (PMID:17060314)
• Vav phosphorylation correlates with calcium flux and Itk phosphorylation during mitogenic CD28 signalaing in Jurkat cells (PMID:17237383)
• Active signals from transgenic Tec kinase (ITK) regulate the development of memory-like CD8+ T cells with innate function. (PMID:17724684)
• Itk autophosphorylation on Y180 within the SH3 domain occurs exclusively via an intramolecular, in cis mechanism (PMID:17897671)
• In transgenic mice specifically lacking Itk kinase activity, active kinase signaling is required for control of T helper (Th)2 cell responses and development of allergic asthma. (PMID:18322190)
• These data suggest that inhibition of ITK blocks HIV infection by affecting multiple steps of HIV replication. (PMID:18443296)
• Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for seasonal allergic rhinitis. (PMID:19222422)
• ITK deficiency as a result of a R335W missense mutation, causes a novel immunodeficiency syndrome that leads to a fatal inadequate immune response to Epstein-Barr virus. (PMID:19425169)
• The authors identify the residues on the surface of the Itk SH2 domain responsible for substrate docking and show that this SH2 surface mediates autophosphorylation in the full-length Itk molecule. (PMID:19523959)
• Findings identify ITK-SYK as an active, transforming FTK and suggest ITK-SYK as a rational therapeutic target for t(5;9)(q33;q22)-positive lymphomas. (PMID:19535334)
• these results provide an initial step in understanding the biological role of Itk-TFII-I signaling in T-cell function. (PMID:19701889)
• Data show that tacrolimus modified the expression levels of Foxp3-regulated T cell receptor signal related-genes, PTPN22 and Itk, in Treg cells. (PMID:19714314)
• The Tec family kinase Itk exists as a folded monomer in vivo. (PMID:19717557)
• TSAd, through its interaction with both Itk and Lck, primes Itk for Lck mediated phosphorylation and thereby regulates CXCL12 induced T cell migration and actin cytoskeleton rearrangements (PMID:20305788)
• Expression of patient-derived ITK in mice induces highly malignant peripheral T cell lymphomas. (PMID:20439541)
• T-cell receptor (TCR)-induced association between ITK and SLP-76, recruitment and transphosphorylation of ITK, actin polarization at the T-cell contact site, and expression of Th2 cytokines (PMID:20457812)
• Knocking down Itk expression inhibits Jurkat cell proliferation and cytokines production. (PMID:21280324)
• People with the -rare allele 196C>T may be more susceptible to asthma via transcriptional regulation of the ITK gene. (PMID:21323647)
• No detrimental mutations were identified in ITK in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. (PMID:21674762)
• These data suggest a sequential mechanism whereby ZAP-70-dependent priming of SLP-76 at three N-terminal sites triggers reciprocal regulatory interactions between Itk and SLP-76, which are ultimately required to couple active Itk to PLC-gamma1. (PMID:21725281)
• ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton’s tyrosine kinase (PMID:22289921)
• These results indicate that Itk is required for efficient replication of influenza virus in infected T-cells. (PMID:22302878)
• This review focuses on Itk and its role in regulating T-cell signaling and function, especially the activation and development of alpha-beta T cells. (PMID:22449075)
• DEF6, a novel substrate for the Tec kinase ITK, contains a glutamine-rich aggregation-prone region and forms cytoplasmic granules that co-localize with P-bodies. (PMID:22829599)
• ITK and Gag colocalized at the plasma membrane and were concentrated at sites of F-actin accumulation and membrane lipid rafts in HIV-1 infected T cells (PMID:23260110)
• Data indicate that the intracellular signaling of ITK-SYK requires both SLP-76 and the adapter function of SYK/ZAP-70 kinases. (PMID:23293025)
• a new pathway regulated by Itk in cells, and suggest cross talk between Itk and G-protein signaling downstream of the TcR. (PMID:23454662)
• Case Report/Letter: ITK/SYK translocation in angioimmunoblastic T-cell lymphoma. (PMID:24076779)
• T-cell-specific human ITK-Syk oncogene in mice leads to early polyclonal T cell lymphoproliferation with B cell expansion. It induces terminal T cell differentiation via Blimp-1, eliminating oncogene-expressing cells early in development. (PMID:24376268)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	itk	ENSDARG00000017565
mus_musculus	Itk	ENSMUSG00000020395
rattus_norvegicus	Itk	ENSRNOG00000006860

Paralogs (32): FGR (ENSG00000000938), MATK (ENSG00000007264), BTK (ENSG00000010671), FYN (ENSG00000010810), STYK1 (ENSG00000060140), TNK2 (ENSG00000061938), TXK (ENSG00000074966), JAK2 (ENSG00000096968), ABL1 (ENSG00000097007), PTK6 (ENSG00000101213), HCK (ENSG00000101336), BMX (ENSG00000102010), CSK (ENSG00000103653), TYK2 (ENSG00000105397), JAK3 (ENSG00000105639), FRK (ENSG00000111816), ZAP70 (ENSG00000115085), PTK2B (ENSG00000120899), SRMS (ENSG00000125508), TEC (ENSG00000135605), BLK (ENSG00000136573), ABL2 (ENSG00000143322), FER (ENSG00000151422), JAK1 (ENSG00000162434), SYK (ENSG00000165025), PTK2 (ENSG00000169398), TNK1 (ENSG00000174292), YES1 (ENSG00000176105), FES (ENSG00000182511), LCK (ENSG00000182866), SRC (ENSG00000197122), LYN (ENSG00000254087)

Protein

Protein identifiers

Tyrosine-protein kinase ITK/TSK — Q08881 (reviewed: Q08881)

Alternative names: Interleukin-2-inducible T-cell kinase, Kinase EMT, T-cell-specific kinase, Tyrosine-protein kinase Lyk

All UniProt accessions (4): Q08881, A0A8V8TLR2, E5RFR5, E5RJY4

UniProt curated annotations — full annotation on UniProt →

Function. Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Required for TCR-mediated calcium response in gamma-delta T-cells, may also be involved in the modulation of the transcriptomic signature in the Vgamma2-positive subset of immature gamma-delta T-cells. Phosphorylates TBX21 at ‘Tyr-530’ and mediates its interaction with GATA3.

Subunit / interactions. Homooligomerizes; this association negatively regulates kinase activity. Interacts with PPIA/CYPA; this interaction regulates TCR signal strength via a proline-directed conformational switch in ITK. Interacts with THEMIS. Interacts with FASLG. Interacts with VAV1; this interaction is important for VAV1 localization and TCR-induced actin polarization. Interacts with TBX21.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. T-cell lines and natural killer cell lines.

Post-translational modifications. Phosphorylated at Tyr-512 in the activation loop of the kinase domain by LCK. Subsequent autophosphorylation at Tyr-180 leads to the kinase activation. The autophosphorylated Tyr-180 lies within the substrate binding sequence of the SH3 domain. Ubiquitinated.

Disease relevance. Lymphoproliferative syndrome 1 (LPFS1) [MIM:613011] A rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The N-terminal PH domain allows ITK to be recruited to the plasma membrane by an activated PI3 kinase. This domain also contains a proline-rich region (PRR). The adjoining domain is a SH3 domain, which binds to PRR (from itself or from other proteins). Next, a SH2 domain is required for binding tyrosine-phosphorylated substrates. In the C-terminal region, the kinase domain is required for tyrosine phosphorylation.

Induction. Through a myriad of surface receptors including the TCR/CD3 signaling complex, coreceptors, or chemokine receptors.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily.

RefSeq proteins (1): NP_005537* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000980	SH2	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001452	SH3_domain	Domain
IPR001562	Znf_Btk_motif	Conserved_site
IPR001849	PH_domain	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR035583	ITK_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR042785	ITK_PTKc	Domain
IPR050198	Non-receptor_tyrosine_kinases	Family

Pfam: PF00017, PF00018, PF00169, PF00779, PF07714

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), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (66 total): strand 19, helix 16, sequence variant 7, binding site 6, turn 5, domain 4, modified residue 3, sequence conflict 2, chain 1, mutagenesis site 1, zinc finger region 1, active site 1

Structure

Experimental structures (PDB)

37 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9NWX	X-RAY DIFFRACTION	1.35
4HCU	X-RAY DIFFRACTION	1.43
4HCT	X-RAY DIFFRACTION	1.48
4HCV	X-RAY DIFFRACTION	1.48
4M15	X-RAY DIFFRACTION	1.52
4M14	X-RAY DIFFRACTION	1.55
3T9T	X-RAY DIFFRACTION	1.65
3MIY	X-RAY DIFFRACTION	1.67
4M0Y	X-RAY DIFFRACTION	1.7
4PQN	X-RAY DIFFRACTION	1.71
3MJ1	X-RAY DIFFRACTION	1.72
4M13	X-RAY DIFFRACTION	1.85
3V5L	X-RAY DIFFRACTION	1.86
3MJ2	X-RAY DIFFRACTION	1.9
3V8T	X-RAY DIFFRACTION	2
4M0Z	X-RAY DIFFRACTION	2
4L7S	X-RAY DIFFRACTION	2.03
3QGW	X-RAY DIFFRACTION	2.1
3QGY	X-RAY DIFFRACTION	2.1
4RFM	X-RAY DIFFRACTION	2.1
4MF1	X-RAY DIFFRACTION	2.11
4M12	X-RAY DIFFRACTION	2.15
4KIO	X-RAY DIFFRACTION	2.18
3V8W	X-RAY DIFFRACTION	2.27
1SM2	X-RAY DIFFRACTION	2.3
4QD6	X-RAY DIFFRACTION	2.45
1SNU	X-RAY DIFFRACTION	2.5
4PP9	X-RAY DIFFRACTION	2.58
3V5J	X-RAY DIFFRACTION	2.59
4MF0	X-RAY DIFFRACTION	2.67

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08881-F1	84.82	0.52

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): 482 (proton acceptor)

Ligand- & substrate-binding residues (6): 143; 369–377; 391; 121; 132; 133

Post-translational modifications (3): 180, 512, 565

Mutagenesis-validated functional residues (1):

Position	Phenotype
288	complete loss of interaction with ppia/cypa.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-202433	Generation of second messenger molecules
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-1280218	Adaptive Immune System
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-202403	TCR signaling
R-HSA-2454202	Fc epsilon receptor (FCERI) signaling

MSigDB gene sets: 382 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, MODULE_255, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, MODULE_317, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, CEBPB_01, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75, FINETTI_BREAST_CANCER_KINOME_GREEN, ATF1_Q6, BRN2_01

GO Biological Process (12): positive regulation of cytokine production (GO:0001819), NK T cell differentiation (GO:0001865), adaptive immune response (GO:0002250), cellular defense response (GO:0006968), signal transduction (GO:0007165), intracellular signal transduction (GO:0035556), T cell activation (GO:0042110), gamma-delta T cell activation (GO:0046629), T cell receptor signaling pathway (GO:0050852), B cell receptor signaling pathway (GO:0050853), immune system process (GO:0002376), protein phosphorylation (GO:0006468)

GO Molecular Function (10): non-membrane spanning protein tyrosine kinase activity (GO:0004715), ATP binding (GO:0005524), zinc ion binding (GO:0008270), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein tyrosine kinase activity (GO:0004713), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Immune System	2
TCR signaling	1
Fc epsilon receptor (FCERI) signaling	1
Adaptive Immune System	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
antigen receptor-mediated signaling pathway	2
cellular anatomical structure	2
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
alpha-beta T cell differentiation	1
immune response	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
lymphocyte activation	1
T cell activation	1
biological_process	1
phosphorylation	1
protein modification process	1
protein tyrosine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein kinase activity	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
membrane	1
cell periphery	1
anchoring junction	1

Protein interactions and networks

STRING

2468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITK	LCP2	Q13094	996
ITK	VAV1	P15498	978
ITK	PLCG1	P19174	954
ITK	CD28	P10747	954
ITK	GRAP2	O75791	949
ITK	NCK1	P16333	926
ITK	GRB2	P29354	901
ITK	SH2D2A	Q9NP31	771
ITK	IFNG	P01579	755
ITK	KIRREL1	Q96J84	717
ITK	KIRREL2	Q6UWL6	717
ITK	LAT	O43561	713
ITK	CD4	P01730	704
ITK	FYB1	O15117	693
ITK	IL2	P01585	689

IntAct

115 interactions, top by confidence:

A	B	Type	Score
ITK	LCP2	psi-mi:“MI:0915”(physical association)	0.730
LCP2	ITK	psi-mi:“MI:0915”(physical association)	0.730
ITK	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.670
ITK	AHNAK	psi-mi:“MI:0915”(physical association)	0.610
ITK	AHNAK	psi-mi:“MI:0407”(direct interaction)	0.610
ITK	Plcg1	psi-mi:“MI:0407”(direct interaction)	0.590
SFN	ITK	psi-mi:“MI:0915”(physical association)	0.560
LCP2	LCK	psi-mi:“MI:0914”(association)	0.560
EGFR	ITK	psi-mi:“MI:0915”(physical association)	0.550
ITK	EGFR	psi-mi:“MI:0915”(physical association)	0.550
FASLG	ITK	psi-mi:“MI:0407”(direct interaction)	0.540
ITK	FASLG	psi-mi:“MI:0915”(physical association)	0.540
FASLG	ITK	psi-mi:“MI:0915”(physical association)	0.540
ITK	GAPDHS	psi-mi:“MI:0914”(association)	0.530
ITK	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
WDCP	PAPSS1	psi-mi:“MI:0914”(association)	0.530
ADAM15	ITK	psi-mi:“MI:0407”(direct interaction)	0.440
ITK	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
ITK	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
ITK	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
ITK	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
ITK	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
ITK	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.440
ITK	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
ITK	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
ITK	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
PDZRN4	ITK	psi-mi:“MI:0407”(direct interaction)	0.440
ITK	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (87): SPRR2A (Reconstituted Complex), ITK (Affinity Capture-MS), ITK (Two-hybrid), NSUN6 (Co-fractionation), ITK (PCA), ITK (Biochemical Activity), HSP90AB3P (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), DYNC1I2 (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS), GAPDHS (Affinity Capture-MS), CDC37 (Affinity Capture-MS), KPNA2 (Two-hybrid), KPNA2 (Biochemical Activity), ITK (Affinity Capture-Western)

ESM2 similar proteins: F1RDG9, G5EE56, O45539, P00523, P00524, P00525, P00526, P00528, P05480, P06241, P09769, P12931, P13115, P13116, P13406, P14084, P14085, P14234, P16277, P17713, P24604, P25020, P27446, P27447, P31693, P32577, P35991, P41239, P41240, P41241, P42680, P42681, P42682, P42685, P42686, P42690, P51451, P63185, Q05876, Q06187

Diamond homologs: A0JNB0, A1A5H8, A1Y2K1, F1LM93, F1RDG9, G5EE56, O45539, P00519, P00520, P00521, P00522, P00523, P00524, P00525, P00526, P00527, P00528, P00544, P03949, P05480, P06239, P06240, P06241, P07947, P07948, P08103, P08630, P08631, P09324, P09769, P10447, P10936, P12931, P13115, P13116, P13406, P14084, P14085, P14234, P15054

SIGNOR signaling

23 interactions.

A	Effect	B	Mechanism
ITK	“up-regulates activity”	ITK	phosphorylation
ITK	up-regulates	SIGLEC10	phosphorylation
ITK	up-regulates	PLCG1	phosphorylation
ITK	up-regulates	CD28	phosphorylation
ITK	“up-regulates activity”	HAVCR2	phosphorylation
PTPN11	“down-regulates activity”	ITK	dephosphorylation
ITK	“up-regulates activity”	GNA13	phosphorylation
BTK	up-regulates	ITK	phosphorylation
ITK	up-regulates	TEC	phosphorylation
ITK	“up-regulates activity”	BMX	phosphorylation
ITK	“down-regulates activity”	BTK	phosphorylation
ITK	“up-regulates activity”	CD28	phosphorylation
LCK	up-regulates	ITK	phosphorylation
“pazopanib hydrochloride”	“down-regulates activity”	ITK	“chemical inhibition”
9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone	“down-regulates activity”	ITK	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 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
Signaling by ERBB2 ECD mutants	5	51.7×	4e-06
Ras activation upon Ca2+ influx through NMDA receptor	5	43.9×	6e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	41.8×	6e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	41.8×	6e-06
Signaling by ERBB2 KD Mutants	6	39.0×	1e-06
Long-term potentiation	5	36.6×	1e-05
Signaling by ERBB2 TMD/JMD mutants	5	36.6×	1e-05
Assembly and cell surface presentation of NMDA receptors	9	35.1×	1e-09

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	63.8×	7e-12
receptor clustering	7	53.3×	1e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	8	48.4×	1e-09
protein localization to synapse	5	46.7×	7e-06
epidermal growth factor receptor signaling pathway	6	18.1×	8e-05
phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	12.8×	2e-03
cell surface receptor protein tyrosine kinase signaling pathway	6	12.7×	4e-04
cell-cell adhesion	10	12.4×	1e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	6
Uncertain significance	273
Likely benign	244
Benign	44

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1456681	NM_005546.4(ITK):c.49C>T (p.Gln17Ter)	Pathogenic
1460222	NC_000005.9:g.(?156659330)(156667225_?)del	Pathogenic
2004689	NM_005546.4(ITK):c.228T>A (p.Tyr76Ter)	Pathogenic
2088804	NM_005546.4(ITK):c.380del (p.Asp127fs)	Pathogenic
2109594	NM_005546.4(ITK):c.1201G>T (p.Glu401Ter)	Pathogenic
2109769	NM_005546.4(ITK):c.1664del (p.Gly555fs)	Pathogenic
2148272	NM_005546.4(ITK):c.742A>T (p.Lys248Ter)	Pathogenic
2750136	NM_005546.4(ITK):c.389G>A (p.Trp130Ter)	Pathogenic
3251232	NM_005546.4(ITK):c.929del (p.Lys310fs)	Pathogenic
3257570	NM_005546.4(ITK):c.929_930delinsT (p.Lys310fs)	Pathogenic
3661212	NM_005546.4(ITK):c.871A>T (p.Lys291Ter)	Pathogenic
3667792	NM_005546.4(ITK):c.925G>T (p.Glu309Ter)	Pathogenic
4694433	NM_005546.4(ITK):c.175C>T (p.Arg59Ter)	Pathogenic
4725764	NM_005546.4(ITK):c.819C>G (p.Tyr273Ter)	Pathogenic
521210	NM_005546.4(ITK):c.913del (p.Tyr305fs)	Pathogenic
64371	NM_005546.4(ITK):c.1764C>G (p.Tyr588Ter)	Pathogenic
12741	NM_005546.4(ITK):c.1003C>T (p.Arg335Trp)	Likely pathogenic
2860481	NM_005546.4(ITK):c.139-2A>G	Likely pathogenic
3064392	NM_005546.4(ITK):c.129del (p.Arg44fs)	Likely pathogenic
4731821	NM_005546.4(ITK):c.455-1G>C	Likely pathogenic
4846822	NM_005546.4(ITK):c.1233-1G>A	Likely pathogenic
64372	NM_005546.4(ITK):c.86G>A (p.Arg29His)	Likely pathogenic

SpliceAI

2449 predictions. Top by Δscore:

Variant	Effect	Δscore
5:157163666:A:T	acceptor_gain	1.0000
5:157165562:CCA:C	donor_gain	1.0000
5:157181113:GGG:G	donor_gain	1.0000
5:157181114:GG:G	donor_gain	1.0000
5:157181114:GGG:G	donor_gain	1.0000
5:157181115:GG:G	donor_gain	1.0000
5:157181116:GTAT:G	donor_gain	1.0000
5:157181117:T:G	donor_loss	1.0000
5:157208887:A:AG	acceptor_gain	1.0000
5:157208888:G:GT	acceptor_gain	1.0000
5:157208888:GA:G	acceptor_gain	1.0000
5:157208888:GAA:G	acceptor_gain	1.0000
5:157208888:GAAGA:G	acceptor_gain	1.0000
5:157208991:CAGG:C	donor_loss	1.0000
5:157208994:G:GA	donor_loss	1.0000
5:157208995:T:G	donor_loss	1.0000
5:157211365:GAAG:G	donor_gain	1.0000
5:157211370:T:G	donor_loss	1.0000
5:157212331:GA:G	donor_gain	1.0000
5:157212332:A:G	donor_gain	1.0000
5:157217865:A:AG	acceptor_gain	1.0000
5:157217866:G:GA	acceptor_gain	1.0000
5:157217906:GG:G	donor_gain	1.0000
5:157217907:GG:G	donor_gain	1.0000
5:157222858:CCCAG:C	acceptor_loss	1.0000
5:157222859:CCAGC:C	acceptor_loss	1.0000
5:157222860:CAG:C	acceptor_loss	1.0000
5:157222861:A:AG	acceptor_gain	1.0000
5:157222862:G:GA	acceptor_gain	1.0000
5:157222862:GC:G	acceptor_gain	1.0000

AlphaMissense

4085 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:157181016:G:C	K13N	1.000
5:157181016:G:T	K13N	1.000
5:157232341:T:A	W239R	1.000
5:157232341:T:C	W239R	1.000
5:157243682:T:C	F374L	1.000
5:157243684:T:A	F374L	1.000
5:157243684:T:G	F374L	1.000
5:157243735:A:C	K391N	1.000
5:157243735:A:T	K391N	1.000
5:157244471:G:C	R481T	1.000
5:157244471:G:T	R481I	1.000
5:157244474:A:C	D482A	1.000
5:157244474:A:T	D482V	1.000
5:157245775:A:C	D500A	1.000
5:157245775:A:G	D500G	1.000
5:157245775:A:T	D500V	1.000
5:157245776:C:A	D500E	1.000
5:157245776:C:G	D500E	1.000
5:157245936:T:A	W524R	1.000
5:157245936:T:C	W524R	1.000
5:157245938:G:C	W524C	1.000
5:157245938:G:T	W524C	1.000
5:157181014:A:G	K13E	0.999
5:157211347:T:A	W102R	0.999
5:157211347:T:C	W102R	0.999
5:157214253:T:A	W130R	0.999
5:157214253:T:C	W130R	0.999
5:157232371:G:C	A249P	0.999
5:157238118:G:A	G260R	0.999
5:157238118:G:C	G260R	0.999

dbSNP variants (sampled 300 via entrez): RS1000063941 (5:157249957 T>G), RS1000065259 (5:157237847 A>T), RS1000161290 (5:157200214 T>G), RS1000179129 (5:157215950 C>T), RS1000219136 (5:157230054 T>A,C), RS1000303925 (5:157204616 T>C), RS1000329991 (5:157232795 C>T), RS1000331834 (5:157250311 T>C), RS1000354059 (5:157221710 T>A,C,G), RS1000360964 (5:157183440 G>T), RS1000371463 (5:157188966 T>G), RS1000487055 (5:157188683 C>A,T), RS1000514735 (5:157233268 C>A), RS1000545715 (5:157232897 C>A), RS1000597433 (5:157194280 C>T)

Disease associations

OMIM: gene MIM:186973 | disease phenotypes: MIM:613011, MIM:606579, MIM:601859

GenCC curated gene-disease

Disease	Classification	Inheritance
lymphoproliferative syndrome 1	Definitive	Autosomal recessive
lymphoproliferative syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
lymphoproliferative syndrome 1	Definitive	AR

Mondo (5): lymphoproliferative syndrome 1 (MONDO:0013081), autoinflammatory syndrome (MONDO:0019751), vitiligo-associated multiple autoimmune disease susceptibility 1 (MONDO:0011684), autoimmune lymphoproliferative syndrome type 1 (MONDO:0011158), lymphoproliferative syndrome (MONDO:0016537)

Orphanet (5): Combined immunodeficiency due to CD27 deficiency (Orphanet:238505), Combined immunodeficiency due to ITK deficiency (Orphanet:538963), Autoinflammatory syndrome (Orphanet:93665), OBSOLETE: Vitiligo-associated autoimmune disease (Orphanet:247871), Autoimmune lymphoproliferative syndrome (Orphanet:3261)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001698	Pericardial effusion
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001876	Pancytopenia
HP:0001882	Decreased total leukocyte count
HP:0001890	Autoimmune hemolytic anemia
HP:0001903	Anemia
HP:0001954	Recurrent fever
HP:0001973	Autoimmune thrombocytopenia
HP:0002202	Pleural effusion
HP:0002240	Hepatomegaly
HP:0002716	Lymphadenopathy
HP:0002719	Recurrent infections
HP:0002960	Autoimmunity
HP:0003281	Increased circulating ferritin concentration
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0003621	Juvenile onset
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0004315	Decreased circulating IgG concentration
HP:0005523	Lymphoproliferative disorder
HP:0010280	Stomatitis
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0011463	Childhood onset
HP:0012156	Hemophagocytosis
HP:0012189	Hodgkin lymphoma
HP:0012191	B-cell lymphoma
HP:0020072	Persistent EBV viremia
HP:0032218	Decreased CD4+ T cell proportion

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000995_6	Personality traits in bipolar disorder	1.000000e-06
GCST003518_6	Daytime sleep phenotypes	7.000000e-06
GCST006979_168	Heel bone mineral density	3.000000e-10
GCST009798_48	Asthma	2.000000e-10
GCST010500_5	T-Cell Immunoglobulin and Mucin domain 1 levels	8.000000e-12
GCST90002381_400	Eosinophil count	5.000000e-11
GCST90014325_24	Asthma	8.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004365	personality trait
EFO:0007828	daytime rest measurement
EFO:0009270	heel bone mineral density
EFO:0010812	T-cell immunoglobulin and mucin domain 1 measurement
EFO:0004842	eosinophil count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008232	Lymphoproliferative Disorders	C15.604.515; C20.683.515
C567815	Lymphoproliferative Syndrome, Ebv-Associated, Autosomal, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2959 (SINGLE PROTEIN), CHEMBL4296642 (PROTEIN FAMILY), CHEMBL5465213 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

39 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 174,831 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1873475	IBRUTINIB	4	7,994
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3707348	ACALABRUTINIB	4	4,504
CHEMBL3936761	ZANUBRUTINIB	4	2,484
CHEMBL4085457	RITLECITINIB	4	708
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL4072833	EVOBRUTINIB	3	960
CHEMBL4483575	REMIBRUTINIB	3	569
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL124660	TANDUTINIB	2	2,530
CHEMBL1721885	SU-014813	2	363
CHEMBL1738757	REBASTINIB	2
CHEMBL1967878	CENISERTIB	2
CHEMBL1980297	ILORASERTIB	2
CHEMBL253969	OSI-632	2
CHEMBL3301625	SPEBRUTINIB	2
CHEMBL3900554	BMS-986142	2
CHEMBL4094440	BMS-919373	2
CHEMBL4114766	ATUZABRUTINIB	2
CHEMBL4116008	CERDULATINIB	2
CHEMBL4297674	BRANEBRUTINIB	2

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Tec family

Most potent curated ligand interactions (11 total), top 11:

Ligand	Action	Affinity	Parameter
GNE-4997	Inhibition	10.05	pKi
modzatinib	Inhibition	9.74	pIC50
compound 7 [PMID: 22464456]	Inhibition	9.52	pIC50
PRN694	Inhibition	9.52	pIC50
ibrutinib	Inhibition	8.31	pIC50
soquelitinib	Inhibition	8.0	pIC50
BMS-509744	Inhibition	7.72	pIC50
WZ4002	Inhibition	7.37	pKd
compound 4g [PMID: 21316219]	Inhibition	7.22	pIC50
compound 25 [PMID: 31260299]	Inhibition	6.51	pIC50
acalabrutinib	Inhibition	6.0	pIC50

Binding affinities (BindingDB)

327 measured of 591 human assays (591 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-1-hydroxypropan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide	IC50	0.04 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide	IC50	0.05 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
(R)-N-(1-((1-acryloylpyrrolidin-2-yl)methyl)-5-(((cyclopropylmethyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide	IC50	0.08 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((R)-1-hydroxypropan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide	IC50	0.09 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
(R)-N-(1-((1-acryloylpyrrolidin-2-yl)methyl)-5-(((2-hydroxy-2-methylpropyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide	IC50	0.09 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((R)-1-hydroxy-3,3-dimethylbutan-2-yl)-amino)-methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide	IC50	0.1 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethyl-butan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide	IC50	0.3 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
5-(5-cyclopropyl-1H-pyrazol-4-yl)-N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]thiophene-2-carboxamide	IC50	0.59 nM	US-10752615: Spirocyclic containing compounds and pharmaceutical uses thereof
N-[1-(1-prop-2-enoylpiperidin-3-yl)benzimidazol-2-yl]-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide	IC50	0.6 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
5-(difluoromethyl)-N-[5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]-1-[[(2R)-1-prop-2-enoylpyrrolidin-2-yl]methyl]benzimidazol-2-yl]thiophene-2-carboxamide	IC50	0.6 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((R)-1-hydroxy-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)-thiophene-2-carboxamide formate	IC50	0.6 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
N-[5-(hydroxymethyl)-1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]-5-(2-oxopiperidin-4-yl)thiophene-2-carboxamide	IC50	0.64 nM	US-10752615: Spirocyclic containing compounds and pharmaceutical uses thereof
5-(5-methyl-1H-pyrazol-4-yl)-N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]thiophene-2-carboxamide	IC50	0.78 nM	US-10752615: Spirocyclic containing compounds and pharmaceutical uses thereof
N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-1-hydroxy-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide formate	IC50	0.8 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-1-hydroxypropan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)-thiophene-2-carboxamide formate	IC50	0.8 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
N-1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((R)-1-methoxypropan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)-thiophene-2-carboxamide formate	IC50	0.8 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
IBRUTINIB	IC50	0.8 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiophene-2-carboxamide	IC50	0.89 nM	US-10752615: Spirocyclic containing compounds and pharmaceutical uses thereof
N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((R)-1-hydroxypropan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)-thiophene-2-carboxamide formate	IC50	0.9 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide	IC50	0.99 nM	US-10752615: Spirocyclic containing compounds and pharmaceutical uses thereof
(R)-N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((cyclopropyl-methyl)-amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide	IC50	1.1 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiophene-2-carboxamide	IC50	1.1 nM	US-10752615: Spirocyclic containing compounds and pharmaceutical uses thereof
N-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl]prop-2-enamide	IC50	1.1 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
N-[1-[[(2R)-1-[(E)-2-cyano-3-(3-methyloxetan-3-yl)prop-2-enoyl]pyrrolidin-2-yl]methyl]-5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]benzimidazol-2-yl]-5-(difluoromethyl)thiophene-2-carboxamide	IC50	1.3 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
(R)-N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide	IC50	1.4 nM	US-9932329: Benzimidazole derivatives as RLK and ITK inhibitors
Staurosporine	KD	1.7 nM
N-[1-[1-[(E)-4-(dimethylamino)but-2-enoyl]piperidin-3-yl]benzimidazol-2-yl]-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide	IC50	1.8 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
5-amino-1-[(3R)-1-[(E)-4-methoxybut-2-enoyl]pyrrolidin-3-yl]-3-(4-phenoxyphenyl)pyrazole-4-carboxamide	IC50	1.9 nM	US-10112922: Inhibitor of bruton’s tyrosine kinase
1-[(2S)-2-[[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]prop-2-en-1-one	IC50	2.3 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
N-[1-[[(2R)-1-[(E)-5-amino-2-cyano-4,4-dimethylpent-2-enoyl]pyrrolidin-2-yl]methyl]benzimidazol-2-yl]-5-(difluoromethyl)thiophene-2-carboxamide	IC50	2.3 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
N-[1-[[(2R)-1-[(E)-2-cyano-4,4-dimethylpent-2-enoyl]pyrrolidin-2-yl]methyl]-5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]benzimidazol-2-yl]-5-(difluoromethyl)thiophene-2-carboxamide	IC50	2.4 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
N-[1-[[(2R)-1-[(E)-2-cyano-4-methylpent-2-enoyl]pyrrolidin-2-yl]methyl]-5-[(2,2-dimethylpropylamino)methyl]benzimidazol-2-yl]-1,2-oxazole-5-carboxamide	IC50	2.6 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
5-(6-oxo-3H-pyridin-3-yl)-N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]thiophene-2-carboxamide	IC50	2.95 nM	US-10752615: Spirocyclic containing compounds and pharmaceutical uses thereof
N-[1-[1-[(E)-2-cyano-4-(dimethylamino)-4-methylpent-2-enoyl]piperidin-3-yl]benzimidazol-2-yl]-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide	IC50	3 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
AVL-292	IC50	3.2 nM	US-9975882: Heteroaromatic compounds as BTK inhibitors
N-[1-[[(2R)-1-[(E)-2-cyano-3-cyclopropylprop-2-enoyl]pyrrolidin-2-yl]methyl]-5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]benzimidazol-2-yl]-5-(difluoromethyl)thiophene-2-carboxamide	IC50	3.5 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
N-[(3S)-1-Acryloyl-3-pyrrolidinyl]-4-{[cis-2,6-dimethyl-4-morpholinyl]methyl}-N’-[1,3]thiazolo[5,4-b]pyridin-2-yl-2,6-pyridinediamine (9)	IC50	5 nM
N-[1-[2-[[(E)-2-cyano-4-methylpent-2-enoyl]amino]ethyl]benzimidazol-2-yl]-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide	IC50	5 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
N-[1-[[(2R)-1-[(E)-2-cyano-4-methylpent-2-enoyl]pyrrolidin-2-yl]methyl]-5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]benzimidazol-2-yl]-5-(difluoromethyl)thiophene-2-carboxamide	IC50	5 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
N-[(3S)-1-Acryloyl-3-pyrrolidinyl]-N’-[1,3]thiazolo[5,4-b]pyridin-2-yl-4-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)-2,6-pyridinediamine (12)	IC50	5 nM
N-[1-[[(2R)-1-[(E)-2-cyano-4-ethoxy-4-methylpent-2-enoyl]pyrrolidin-2-yl]methyl]-5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]benzimidazol-2-yl]-5-(difluoromethyl)thiophene-2-carboxamide	IC50	5.4 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
N-[1-[[1-[(E)-2-cyano-4-methylpent-2-enoyl]pyrrolidin-2-yl]methyl]-5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]benzimidazol-2-yl]-5-(difluoromethyl)thiophene-2-carboxamide	IC50	5.6 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
N-[1-[[(2R)-1-[(E)-2-cyano-3-(3-methyloxetan-3-yl)prop-2-enoyl]pyrrolidin-2-yl]methyl]-5-[(2,2-dimethylpropylamino)methyl]benzimidazol-2-yl]-1,2-oxazole-5-carboxamide	IC50	6 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
(S)-1-(3-((4-(Piperidin-1-ylmethyl)-6-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one (10)	IC50	6.3 nM
N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]-5-(1H-pyrrolo[2,3-c]pyridin-4-yl)thiophene-2-carboxamide	IC50	6.49 nM	US-10752615: Spirocyclic containing compounds and pharmaceutical uses thereof
4-chloro-N-[5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]-1-[(1-prop-2-enoylpyrrolidin-2-yl)methyl]benzimidazol-2-yl]benzamide	IC50	7 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
4-chloro-N-[5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]-1-[[(2R)-1-prop-2-enoylpyrrolidin-2-yl]methyl]benzimidazol-2-yl]benzamide	IC50	7 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
N-[1-[[(2R)-1-[(E)-2-cyano-4-methylpent-2-enoyl]pyrrolidin-2-yl]methyl]-5-[(2,2-dimethylpropylamino)methyl]benzimidazol-2-yl]-5-(difluoromethyl)thiophene-2-carboxamide	IC50	7.5 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
N-[1-[[(2R)-1-[(E)-2-cyano-4-methylpent-2-enoyl]pyrrolidin-2-yl]methyl]-5-[(2-methylpropylamino)methyl]benzimidazol-2-yl]-5-(difluoromethyl)thiophene-2-carboxamide	IC50	7.6 nM	US-9573958: Benzimidazole derivatives as ITK inhibitors
1-((S)-3-((4-((((R)-3,3-Dimethylbutan-2-yl)amino)methyl)-6-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one (13)	IC50	7.9 nM

ChEMBL bioactivities

1990 potent at pChembl≥5 of 2049 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.40	IC50	0.04	nM	CHEMBL5913558
10.30	IC50	0.05	nM	CHEMBL5945729
10.10	IC50	0.08	nM	CHEMBL5878223
10.05	Ki	0.09	nM	CHEMBL3426309
10.05	IC50	0.09	nM	CHEMBL5778702
10.05	IC50	0.09	nM	CHEMBL5751446
10.00	Ki	0.1	nM	CHEMBL3263053
10.00	IC50	0.1	nM	CHEMBL5822312
9.77	Ki	0.17	nM	CHEMBL3355737
9.70	Ki	0.1995	nM	CHEMBL2441275
9.70	Ki	0.2	nM	CHEMBL3298373
9.70	Ki	0.2	nM	CHEMBL3426308
9.70	Ki	0.2	nM	CHEMBL3426302
9.70	Ki	0.2	nM	CHEMBL3426305
9.64	Ki	0.23	nM	CHEMBL3263055
9.60	Ki	0.2512	nM	CHEMBL2441276
9.60	Ki	0.2512	nM	CHEMBL2441274
9.57	Ki	0.27	nM	CHEMBL3355728
9.54	IC50	0.29	nM	CHEMBL5846327
9.52	IC50	0.3	nM	CHEMBL2017556
9.52	Ki	0.3	nM	CHEMBL3287196
9.52	Ki	0.3	nM	CHEMBL3426307
9.52	Ki	0.3	nM	CHEMBL3426303
9.52	Ki	0.3	nM	CHEMBL3426305
9.52	Ki	0.3	nM	CHEMBL3426304
9.52	IC50	0.3	nM	CHEMBL6043359
9.50	Ki	0.3162	nM	CHEMBL2441271
9.47	IC50	0.34	nM	CHEMBL4203077
9.42	Ki	0.38	nM	CHEMBL3355738
9.40	Ki	0.3981	nM	CHEMBL2441270
9.39	IC50	0.41	nM	CHEMBL4219011
9.30	Ki	0.5	nM	CHEMBL3086538
9.30	Ki	0.5	nM	CHEMBL3426301
9.30	Ki	0.5	nM	CHEMBL3426306
9.30	IC50	0.5	nM	CHEMBL4464404
9.29	IC50	0.51	nM	CHEMBL5892177
9.29	IC50	0.51	nM	CHEMBL6064773
9.28	IC50	0.53	nM	CHEMBL4206765
9.25	Ki	0.56	nM	CHEMBL3263050
9.24	IC50	0.58	nM	CHEMBL4214683
9.23	IC50	0.59	nM	CHEMBL5916137
9.22	Ki	0.6	nM	CHEMBL3086535
9.22	IC50	0.6	nM	CHEMBL5930078
9.22	IC50	0.6	nM	CHEMBL4541397
9.22	IC50	0.6	nM	CHEMBL5972380
9.20	Ki	0.631	nM	CHEMBL2441273
9.19	IC50	0.64	nM	CHEMBL4216529
9.19	IC50	0.64	nM	CHEMBL5996989
9.17	IC50	0.67	nM	CHEMBL4207292
9.17	IC50	0.67	nM	CHEMBL5884165

PubChem BioAssay actives

1217 with measured affinity, of 2955 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
Ritlecitinib	1802326: TR-FRET Competition Assay from Article 10.1021/acschembio.6b00677: “Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition.”	ki	<0.0001	uM
N-[1-[(1S)-3-(dimethylamino)-1-phenylpropyl]pyrazol-4-yl]-6-(1H-pyrazol-4-yl)-1H-indazole-3-carboxamide	1141846: Inhibition of full-length ITK (unknown origin) using biotin-EQEDEPEGIYGVLF-NH2 as substrate by plate reader analysis	ki	0.0001	uM
5a-methyl-N-[1-(2-methylsulfonyl-1-pyridin-3-ylethyl)pyrazol-4-yl]-4,4a,5,6-tetrahydro-1H-cyclopropa[f]indazole-3-carboxamide	1154712: Inhibition of ITK (unknown origin) using Acetyl-EFPIYDFLPAKKK-NH2 peptide as substrate after 1 hr by LC-MS analysis	ki	0.0001	uM
(4aS,5aR)-N-[1-[(R)-[(2R)-1,1-dioxothian-2-yl]-phenylmethyl]pyrazol-4-yl]-5,5-difluoro-5a-methyl-1,4,4a,6-tetrahydrocyclopropa[f]indazole-3-carboxamide	1206325: Inhibition of GST-tagged recombinant full length human ITK using AcEFPIYDFLPAKKK-NH2 as substrate after 35 mins by Morrison plot analysis	ki	0.0001	uM
N-[1-[(S)-(1,1-dioxothian-3-yl)-phenylmethyl]pyrazol-4-yl]-6,6-dimethyl-1,4,5,7-tetrahydroindazole-3-carboxamide	1206325: Inhibition of GST-tagged recombinant full length human ITK using AcEFPIYDFLPAKKK-NH2 as substrate after 35 mins by Morrison plot analysis	ki	0.0002	uM
6,6-dimethyl-N-[1-[(S)-(1-oxothian-4-yl)-phenylmethyl]pyrazol-4-yl]-1,4,5,7-tetrahydroindazole-3-carboxamide	1206325: Inhibition of GST-tagged recombinant full length human ITK using AcEFPIYDFLPAKKK-NH2 as substrate after 35 mins by Morrison plot analysis	ki	0.0002	uM
(4aS,5aR)-N-[1-[(S)-(1,1-dioxothian-4-yl)-phenylmethyl]pyrazol-4-yl]-5a-methyl-4,4a,5,6-tetrahydro-1H-cyclopropa[f]indazole-3-carboxamide	1206325: Inhibition of GST-tagged recombinant full length human ITK using AcEFPIYDFLPAKKK-NH2 as substrate after 35 mins by Morrison plot analysis	ki	0.0002	uM
4-[[4-benzyl-6-[(5-methoxy-[1,3]thiazolo[5,4-b]pyridin-2-yl)amino]pyrimidin-2-yl]amino]cyclohexan-1-ol	777301: Inhibition of recombinant human FLAG-tagged ITK using biotinylated GST-SAM68 as substrate after 30 mins	ki	0.0002	uM
N-[1-[(1R)-2-hydroxy-2-methyl-1-phenylpropyl]pyrazol-4-yl]-6-(1H-pyrazol-4-yl)-1H-indazole-3-carboxamide	1141846: Inhibition of full-length ITK (unknown origin) using biotin-EQEDEPEGIYGVLF-NH2 as substrate by plate reader analysis	ki	0.0002	uM
6,6-dimethyl-N-[1-[(S)-phenyl(piperidin-4-yl)methyl]pyrazol-4-yl]-1,4,5,7-tetrahydroindazole-3-carboxamide	1224470: Inhibition of GST-tagged full length ITK (unknown origin) using BLK peptide as substrate after 35 mins	ki	0.0002	uM
4-[[4-(benzenesulfonyl)-6-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]amino]cyclohexan-1-ol	1173756: Inhibition of GST-tagged full-length ITK (unknown origin) using Ac-EFPIYDFLPAKKK-NH2 as substrate after 35 mins by LC/MS analysis	ki	0.0002	uM
4-[[4-(benzenesulfonyl)-6-[(5-methyl-1,3-thiazol-2-yl)amino]-2-pyridinyl]amino]cyclohexan-1-ol	1173756: Inhibition of GST-tagged full-length ITK (unknown origin) using Ac-EFPIYDFLPAKKK-NH2 as substrate after 35 mins by LC/MS analysis	ki	0.0003	uM
N-[1-[(R)-(1,1-dioxothian-2-yl)-phenylmethyl]pyrazol-4-yl]-6,6-dimethyl-1,4,5,7-tetrahydroindazole-3-carboxamide	1206325: Inhibition of GST-tagged recombinant full length human ITK using AcEFPIYDFLPAKKK-NH2 as substrate after 35 mins by Morrison plot analysis	ki	0.0003	uM
N-[1-[(S)-(1,1-dioxothian-4-yl)-phenylmethyl]pyrazol-4-yl]-6,6-dimethyl-1,4,5,7-tetrahydroindazole-3-carboxamide	1206325: Inhibition of GST-tagged recombinant full length human ITK using AcEFPIYDFLPAKKK-NH2 as substrate after 35 mins by Morrison plot analysis	ki	0.0003	uM
N-[5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]-1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]-5-(1,3-oxazol-5-yl)thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0003	uM
3-[2-[5-(difluoromethyl)-1H-thieno[3,2-c]pyrazol-3-yl]-1H-indol-6-yl]pentan-3-ol	657101: Inhibition of recombinant N-terminus His6 tagged Itk (357-620) autophosphorylation expressed in insect Sf9 cells using [33P]ATP by scintillation counting	ic50	0.0003	uM
2-[[6-benzyl-2-[(4-hydroxycyclohexyl)amino]pyrimidin-4-yl]amino]-1,3-benzothiazole-6-carbonitrile	777301: Inhibition of recombinant human FLAG-tagged ITK using biotinylated GST-SAM68 as substrate after 30 mins	ki	0.0003	uM
4-[[4-benzyl-6-([1,3]thiazolo[5,4-b]pyridin-2-ylamino)pyrimidin-2-yl]amino]cyclohexan-1-ol	777301: Inhibition of recombinant human FLAG-tagged ITK using biotinylated GST-SAM68 as substrate after 30 mins	ki	0.0003	uM
N-(1-benzylpyrazol-4-yl)-5,5-difluoro-5a-methyl-1,4,4a,6-tetrahydrocyclopropa[f]indazole-3-carboxamide	1206325: Inhibition of GST-tagged recombinant full length human ITK using AcEFPIYDFLPAKKK-NH2 as substrate after 35 mins by Morrison plot analysis	ki	0.0003	uM
N-[1-[[1-(2-fluoroethyl)azetidin-3-yl]-phenylmethyl]pyrazol-4-yl]-6,6-dimethyl-1,4,5,7-tetrahydroindazole-3-carboxamide	1154712: Inhibition of ITK (unknown origin) using Acetyl-EFPIYDFLPAKKK-NH2 peptide as substrate after 1 hr by LC-MS analysis	ki	0.0003	uM
4-[[4-benzyl-6-[(6-chloro-1,3-benzothiazol-2-yl)amino]pyrimidin-2-yl]amino]cyclohexan-1-ol	777301: Inhibition of recombinant human FLAG-tagged ITK using biotinylated GST-SAM68 as substrate after 30 mins	ki	0.0003	uM
4-[[4-(benzenesulfonyl)-6-[(5-cyclohexyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]amino]cyclohexan-1-ol	1173756: Inhibition of GST-tagged full-length ITK (unknown origin) using Ac-EFPIYDFLPAKKK-NH2 as substrate after 35 mins by LC/MS analysis	ki	0.0004	uM
5-[2-(methylamino)-4-pyridinyl]-N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0004	uM
4-[[4-benzyl-6-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyrimidin-2-yl]amino]cyclohexan-1-ol	777301: Inhibition of recombinant human FLAG-tagged ITK using biotinylated GST-SAM68 as substrate after 30 mins	ki	0.0004	uM
N-[1-[(S)-(1,1-dioxothiolan-3-yl)-phenylmethyl]pyrazol-4-yl]-6,6-dimethyl-1,4,5,7-tetrahydroindazole-3-carboxamide	1206325: Inhibition of GST-tagged recombinant full length human ITK using AcEFPIYDFLPAKKK-NH2 as substrate after 35 mins by Morrison plot analysis	ki	0.0005	uM
6,6-dimethyl-N-[1-[(1R)-2-methylsulfonyl-1-phenylethyl]pyrazol-4-yl]-1,4,5,7-tetrahydroindazole-3-carboxamide	1206325: Inhibition of GST-tagged recombinant full length human ITK using AcEFPIYDFLPAKKK-NH2 as substrate after 35 mins by Morrison plot analysis	ki	0.0005	uM
5-(2-oxo-1H-pyridin-4-yl)-N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0005	uM
N-[3-[[2-(4-morpholin-4-ylanilino)-5-pyridin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]phenyl]prop-2-enamide	1551635: Inhibition of recombinant human N-terminal His6-tagged ITK (352 to 617 residues) expressed in baculovirus infected Sf21 insect cells using STK substrate by HTRF assay	ic50	0.0005	uM
trans-(1S,2S)-2-[3-(diethylaminomethyl)-4-methoxyphenyl]-N-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]cyclopropane-1-carboxamide	1054359: Inhibition of full length GST-tagged ITK (unknown origin) using Ac-EFPIYDFLPAKKK-NH2 as substrate after 35 mins by LC/MS analysis	ki	0.0005	uM
N-[5-[[(4-hydroxycyclohexyl)amino]methyl]-1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]-5-(1,3-oxazol-5-yl)thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0006	uM
5-(2-methylpyrimidin-4-yl)-N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0006	uM
N-[1-[(1R)-2-hydroxy-1-phenylethyl]pyrazol-4-yl]-6-(1H-pyrazol-4-yl)-1H-indazole-3-carboxamide	1141846: Inhibition of full-length ITK (unknown origin) using biotin-EQEDEPEGIYGVLF-NH2 as substrate by plate reader analysis	ki	0.0006	uM
4-[[4-benzyl-6-[(6-ethyl-1,3-benzothiazol-2-yl)amino]pyrimidin-2-yl]amino]cyclohexan-1-ol	777301: Inhibition of recombinant human FLAG-tagged ITK using biotinylated GST-SAM68 as substrate after 30 mins	ki	0.0006	uM
2-[4-[(dimethylamino)methyl]phenyl]-N-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]cyclopropane-1-carboxamide	1054359: Inhibition of full length GST-tagged ITK (unknown origin) using Ac-EFPIYDFLPAKKK-NH2 as substrate after 35 mins by LC/MS analysis	ki	0.0006	uM
5-(2-amino-4-pyridinyl)-N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0007	uM
N-[5-(methylamino)-1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]-5-(1,3-oxazol-5-yl)thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0007	uM
N-[5-[[(3-hydroxy-2,2-dimethylpropyl)amino]methyl]-1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]-5-(1,3-oxazol-5-yl)thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0007	uM
trans-(1S,2S)-2-[4-[(dimethylamino)methyl]phenyl]-N-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]cyclopropane-1-carboxamide	1054359: Inhibition of full length GST-tagged ITK (unknown origin) using Ac-EFPIYDFLPAKKK-NH2 as substrate after 35 mins by LC/MS analysis	ki	0.0007	uM
N-[1-[(1S)-3-(dimethylamino)-1-phenylpropyl]pyrazol-4-yl]-6,6-dimethyl-1,4,5,7-tetrahydroindazole-3-carboxamide	1224470: Inhibition of GST-tagged full length ITK (unknown origin) using BLK peptide as substrate after 35 mins	ki	0.0007	uM
N-[1-[(1S)-3-(dimethylamino)-1-(3-methylphenyl)propyl]pyrazol-4-yl]-6,6-dimethyl-1,4,5,7-tetrahydroindazole-3-carboxamide	1224470: Inhibition of GST-tagged full length ITK (unknown origin) using BLK peptide as substrate after 35 mins	ki	0.0007	uM
5-(1,3-oxazol-5-yl)-N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0008	uM
N-[1-[(3-cyanophenyl)methyl]pyrazol-4-yl]-6-(1H-pyrazol-4-yl)-1H-indazole-3-carboxamide	1141846: Inhibition of full-length ITK (unknown origin) using biotin-EQEDEPEGIYGVLF-NH2 as substrate by plate reader analysis	ki	0.0008	uM
N-[1-[(1S)-2-hydroxy-2-methyl-1-phenylpropyl]pyrazol-4-yl]-6-(1H-pyrazol-4-yl)-1H-indazole-3-carboxamide	1141846: Inhibition of full-length ITK (unknown origin) using biotin-EQEDEPEGIYGVLF-NH2 as substrate by plate reader analysis	ki	0.0008	uM
N-[1-[(1R)-2-(dimethylamino)-1-phenylethyl]pyrazol-4-yl]-6,6-dimethyl-1,4,5,7-tetrahydroindazole-3-carboxamide	1224470: Inhibition of GST-tagged full length ITK (unknown origin) using BLK peptide as substrate after 35 mins	ki	0.0008	uM
5-(difluoromethyl)-N-[5-[[(3-hydroxy-2,2-dimethylpropyl)amino]methyl]-1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0009	uM
5-(2-aminopyrimidin-4-yl)-N-[1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0009	uM
N-[1-[(1R)-3-(dimethylamino)-1-phenylpropyl]pyrazol-4-yl]-6-(1H-pyrazol-4-yl)-1H-indazole-3-carboxamide	1141846: Inhibition of full-length ITK (unknown origin) using biotin-EQEDEPEGIYGVLF-NH2 as substrate by plate reader analysis	ki	0.0009	uM
N-[5-fluoro-1-(6-prop-2-enoyl-6-azaspiro[3.4]octan-2-yl)benzimidazol-2-yl]-5-(1,3-oxazol-5-yl)thiophene-2-carboxamide	1384813: Inhibition of ITK (unknown origin) using fluorescently labeled peptide as substrate after 3 hrs by microfluidic mobility shift assay	ic50	0.0010	uM
(2S)-N-[2-[(4aS,5aR)-5,5-difluoro-5a-methyl-1,4,4a,6-tetrahydrocyclopropa[f]indazol-3-yl]-6-methyl-1H-benzimidazol-5-yl]-N-methyl-2-morpholin-4-ylpropanamide	1834414: Inhibition of ITK (unknown origin) using BTK peptide as substrate preincubated for 30 mins followed by addition of substrate and measured after 60 mins by flourescence based plate reader assay	ic50	0.0010	uM
N-[5-[[[(2S)-3,3-dimethylbutan-2-yl]amino]methyl]-1-(2-hydroxy-2-methylpropyl)benzimidazol-2-yl]-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide	414364: Binding affinity to ITK by DELFIA-based molecular assay	ic50	0.0010	uM

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	3
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
cobaltous chloride	increases expression	1
ochratoxin A	decreases expression	1
gallium arsenide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Air Pollutants, Occupational	affects expression	1
Diuron	decreases expression	1
Hydroxychloroquine	affects cotreatment, decreases expression	1
Methotrexate	decreases expression, affects cotreatment	1
Nickel	increases expression	1
Sulfasalazine	affects cotreatment, decreases expression	1
Testosterone	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	decreases methylation	1
Sodium Selenite	decreases expression	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

563 unique, capped per target: 547 binding, 10 functional, 6 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1006237	Binding	Inhibition of ITK by DELPHIA assay	5-Aminomethyl-1H-benzimidazoles as orally active inhibitors of inducible T-cell kinase (Itk). — Bioorg Med Chem Lett
CHEMBL1018829	Functional	Antagonist activity at human ITK expressed in BTK deficient DT40 cells assessed as inhibition of B cell receptor-stimulated calcium influx	5-Aminomethylbenzimidazoles as potent ITK antagonists. — Bioorg Med Chem Lett
CHEMBL4189695	ADMET	Inhibition of recombinant human ITK using Poly(Glu, Tyr) 4:1 as substrate after 1 hr by ELISA	Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrimido[5,4- b]pyrrolizines as Novel Bruton’s Tyrosine Kinase Inhibitors. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8IW	Abcam HCT 116 ITK KO	Cancer cell line	Male
CVCL_B8XS	Abcam MCF-7 ITK KO	Cancer cell line	Female
CVCL_B9L7	Abcam A-549 ITK KO	Cancer cell line	Male
CVCL_ST53	HAP1 ITK (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00033475	PHASE3	COMPLETED	Reduced Immunosuppressive Therapy With or Without Donor White Blood Cells in Treating Patients With Lymphoproliferative Disease After Organ Transplantation
NCT00053053	PHASE3	COMPLETED	Comparison of Nutritional Supplements in Preventing Weight Loss in Patients With Cancer
NCT00058331	PHASE3	COMPLETED	Epoetin Alfa in Treating Anemia in Patients With Solid Tumors
NCT00070382	PHASE3	COMPLETED	Darbepoetin Alfa Compared With Epoetin Alfa in Treating Anemia in Patients Receiving Chemotherapy for Cancer
NCT00516503	PHASE3	COMPLETED	Baclofen-Amitriptyline Hydrochloride-Ketamine Gel in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00661999	PHASE3	COMPLETED	Darbepoetin Alfa With or Without Iron in Treating Anemia Caused By Chemotherapy in Patients With Cancer
NCT00666211	PHASE3	COMPLETED	Opioid Titration Order Sheet or Standard Care in Treating Patients With Cancer Pain
NCT00719563	PHASE3	COMPLETED	American Ginseng in Treating Patients With Fatigue Caused by Cancer
NCT00750009	PHASE3	COMPLETED	Personalized Information or Basic Information in Helping Patients Make Decisions About Participating in a Clinical Trial
NCT03394365	PHASE3	RECRUITING	A Phase 3 Study of Tabelecleucel for Participants With Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease After Failure With Rituximab or Rituximab and Chemotherapy
NCT05431179	PHASE3	WITHDRAWN	A Study of Zilovertamab and Ibrutinib in Patients With Relapsed or Refractory Mantle Cell Lymphoma
NCT00001379	PHASE2	COMPLETED	Treatment and Natural History Study of Lymphomatoid Granulomatosis
NCT00001438	PHASE2	COMPLETED	A Pilot Study of the Combination of Retinoic Acid and Interferon-Alpha2a for the Treatment of Lymphoproliferative Disorders in Children With Immunodeficiency Syndromes
NCT00066469	PHASE2	COMPLETED	Cyclophosphamide, Rituximab, and Either Prednisone or Methylprednisolone in Treating Patients With Lymphoproliferative Disease After Solid Organ Transplantation
NCT00092222	PHASE2	ACTIVE_NOT_RECRUITING	Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity
NCT00255749	PHASE2	COMPLETED	Epoetin Alfa in Treating Patients With Anemia Who Are Undergoing Chemotherapy for Cancer
NCT00387530	PHASE2	WITHDRAWN	Phenylbutyrate and Valganciclovir in Treating Patients With Relapsed or Refractory Epstein-Barr Virus-Positive Cancer
NCT00416624	PHASE2	COMPLETED	Epoetin Alfa or Darbepoetin Alfa in Treating Patients With Anemia Caused by Chemotherapy
NCT00436618	PHASE2	COMPLETED	Everolimus in Treating Patients With Lymphoma That Has Relapsed or Not Responded to Previous Treatment
NCT00621036	PHASE2	WITHDRAWN	Vaccine Therapy and GM-CSF in Treating Patients With CNS Lymphoma
NCT00869323	PHASE2	TERMINATED	Bortezomib and Rituximab in Treating Patients With Post-Transplant Lymphoproliferative Disorders
NCT00992732	PHASE2	TERMINATED	Study of HQK-1004 and Valganciclovir to Treat Epstein-Barr Virus (EBV) - Positive Lymphoid Malignancies or Lymphoproliferative Disorders
NCT01116232	PHASE2	TERMINATED	Sirolimus, Tacrolimus, Thymoglobulin and Rituximab as Graft-versus-Host-Disease Prophylaxis in Patients Undergoing Haploidentical and HLA Partially Matched Donor Hematopoietic Cell Transplantation
NCT01118013	PHASE2	TERMINATED	Donor Stem Cell Transplant in Treating Patients With Relapsed Hematologic Malignancies or Secondary Myelodysplasia Previously Treated With High-Dose Chemotherapy and Autologous Stem Cell Transplant
NCT02579967	PHASE2	RECRUITING	Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
NCT02861417	PHASE2	ACTIVE_NOT_RECRUITING	Busulfan, Fludarabine Phosphate, and Post-Transplant Cyclophosphamide in Treating Patients With Blood Cancer Undergoing Donor Stem Cell Transplant
NCT03258567	PHASE2	RECRUITING	Nivolumab in Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders and EBV-Positive Non-HodgkinLymphomas
NCT03373019	PHASE2	UNKNOWN	Chidamide Combined With R-GDP in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)
NCT03663933	PHASE2	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation
NCT03744676	PHASE2	COMPLETED	A Safety Trial of Lisocabtagene Maraleucel (JCAR017) for Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL) in the Outpatient Setting (TRANSCEND-OUTREACH-007)
NCT03922724	PHASE2	RECRUITING	Allogeneic Hematopoietic Cell Transplantation for Peripheral T Cell Lymphoma
NCT04339777	PHASE2	RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
NCT04463615	PHASE2	COMPLETED	Leflunomide for the Treatment of Relapsed or Refractory CD30+ Lymphoproliferative Disorders
NCT04554914	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate Tabelecleucel in Participants With Epstein Barr Virus (EBV) Associated Diseases
NCT04858256	PHASE2	RECRUITING	Pacritinib in Relapsed/Refractory T-cell Lymphoproliferative Neoplasms
NCT04883437	PHASE2	RECRUITING	Acalabrutinib and Obinutuzumab for the Treatment of Previously Untreated Follicular Lymphoma or Other Indolent Non-Hodgkin Lymphomas
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT06730126	PHASE2	RECRUITING	Study of the ITK Inhibitor Soquelitinib to Reduce Lymphoproliferation and Improve Cytopenias in Autoimmune Lymphoproliferative Syndrome (ALPS)-FAS Patients
NCT00002153	PHASE1	COMPLETED	Topical Use of 4,4’-Dihydroxybenzophenone-2,4-Dinitrophenylhydrazone (A-007) in the Treatment of Advanced Malignancies Including Kaposi’s Sarcoma and Lymphoproliferative Disorders