Top ▲

IL2 inducible T cell kinase

Click here for help

Target id: 2046

Nomenclature: IL2 inducible T cell kinase

Abbreviated Name: ITK

Family: Tec family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 620 5q33.3 ITK IL2 inducible T cell kinase
Mouse - 625 11 B1.1 Itk IL2 inducible T cell kinase
Rat - 626 10 q21 Itk IL2-inducible T-cell kinase
Previous and Unofficial Names Click here for help
EMT | IL2 inducible T-cell kinase | T-cell-specific kinase | Tcsk | tyrosine-protein kinase ITK/TSK | Tyrosine-protein kinase Lyk
Database Links Click here for help
Alphafold Q08881 (Hs), Q03526 (Mm)
BRENDA 2.7.10.2
CATH/Gene3D 2.30.29.30, 3.30.505.10
ChEMBL Target CHEMBL2959 (Hs)
Ensembl Gene ENSG00000113263 (Hs), ENSMUSG00000020395 (Mm), ENSRNOG00000006860 (Rn)
Entrez Gene 3702 (Hs), 16428 (Mm), 363577 (Rn)
Human Protein Atlas ENSG00000113263 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:3702 (Hs), mmu:16428 (Mm), rno:363577 (Rn)
OMIM 186973 (Hs)
Orphanet ORPHA244711 (Hs)
Pharos Q08881 (Hs)
RefSeq Nucleotide NM_005546 (Hs), NM_010583 (Mm), NM_001108825 (Rn)
RefSeq Protein NP_005537 (Hs), NP_034713 (Mm), NP_001102295 (Rn)
SynPHARM 85316 (in complex with BMS-509744)
81635 (in complex with compound 7 [PMID: 22464456])
UniProtKB Q08881 (Hs), Q03526 (Mm)
Wikipedia ITK (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF APO INTERLEUKIN-2 TYROSINE KINASE CATALYTIC DOMAIN
PDB Id:  1SNX
Resolution:  3.2Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of interleukin-2 inducible T-cell kinase (ITK) catalytic domain with thienopyrazolylindole inhibitor 477.
PDB Id:  3V8T
Ligand:  compound 7 [PMID: 22464456]
Resolution:  2.0Å
Species:  Human
References:  12
Image of receptor 3D structure from RCSB PDB
Description:  ITK kinase domain in complex with compound 1 N-{1-[(1,1-dioxo-1-thian-2-yl)(phenyl)methyl]-1H- pyrazol-4-yl}-5,5-difluoro-5a-methyl-1H,4H,4aH,5H,5aH,6H-cyclopropa[f]indazole-3-carboxamide
PDB Id:  4RFM
Ligand:  GNE-4997
Resolution:  2.1Å
Species:  Human
References:  4
Enzyme Reaction Click here for help
EC Number: 2.7.10.2

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
WZ4002 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pKd 16
⤷ pKd 7.4 (Kd 4.3x10-8 M) [16]
GNE-4997 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 10.1 pKi 4
⤷ pKi 10.1 (Ki 9x10-11 M) [4]
compound 7 [PMID: 22464456] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.5 pIC50 12
⤷ pIC50 9.5 (IC50 3x10-10 M) [12]
PRN694 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.5 pIC50 15
⤷ pIC50 9.5 (IC50 3x10-10 M) [15]
ibrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 5
⤷ pIC50 8.3 (IC50 4.9x10-9 M) [5]
soquelitinib Small molecule or natural product Hs Inhibition >8.0 pIC50 11
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [11]
BMS-509744 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 7.7 pIC50 6
⤷ pIC50 7.7 (IC50 1.9x10-8 M) [6]
compound 4g [PMID: 21316219] Small molecule or natural product Hs Inhibition 7.2 pIC50 10
⤷ pIC50 7.2 (IC50 6x10-8 M) [10]
compound 25 [PMID: 31260299] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.5 pIC50 14
⤷ pIC50 6.5 (IC50 3.069x10-7 M) [14]
acalabrutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition <6.0 pIC50 5
⤷ pIC50 <6.0 (IC50 >1x10-6 M) [5]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 7,13
Key to terms and symbols Click column headers to sort
Target used in screen: ITK
Ligand Sp. Type Action Value Parameter
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.9 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.7 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.5 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 6.7 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.6 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.5 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.4 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.3 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,8
Key to terms and symbols Click column headers to sort
Target used in screen: Itk/ITK
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.9 2.5 0.5
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 4.3 4.0 4.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 8.3 88.0 70.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 21.4 8.0 1.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 22.7 15.0 1.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 30.0 21.0 2.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 34.8 24.0 2.0
dorsomorphin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 39.9 54.0 9.0
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 45.4 5.0 0.0
GSK-3 inhibitor IX Small molecule or natural product Hs Inhibitor Inhibition 46.6 22.0 9.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
The TEC family protein tyrosine kinases have been identified as key components of T-cell-receptor activation and signalling. TEC family kinases are expressed predominantly by haematopoietic cells. T cells express ITK, TXK and TEC [2]. ITK inhibition has been extensively expolred as therapeutic option for Th2-driven inflammatory diseases. Despite much effort having been made to discover novel ITK inhibitors, and favourable preclinical discoveries, the majority of the lead compounds have not translated or progressed to the clinic. JTE-051 (structure not disclosed) is currently the only ITK inhibitor under clinical evaluation, and this is being examined in Phase 2 studies as a treatment for rheumatoid arthritis (NCT02919475) and psoriasis (NCT03358290).
Cell Type Associations
Immuno Cell Type:  T cells
References:  2
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Physiological Consequences of Altering Gene Expression Click here for help
ITK knock-down in Jurkat T cells disrupts HIV-1 attachment, fusion and entry into the cells.
Species:  Human
Tissue:  Jurkat T cells.
Technique:  Small hairpin RNA (shRNA)-mediated knockdown.
References:  9
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Lymphoproliferative syndrome 1
Synonyms: Autosomal recessive lymphoproliferative disease [Orphanet: ORPHA238505]
Lymphoproliferative disease [Disease Ontology: DOID:619]
Disease Ontology: DOID:619
OMIM: 613011
Orphanet: ORPHA238505

References

Show »

1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Berg LJ, Finkelstein LD, Lucas JA, Schwartzberg PL. (2005) Tec family kinases in T lymphocyte development and function. Annu Rev Immunol, 23: 549-600. [PMID:15771581]

3. Brown K, Long JM, Vial SC, Dedi N, Dunster NJ, Renwick SB, Tanner AJ, Frantz JD, Fleming MA, Cheetham GM. (2004) Crystal structures of interleukin-2 tyrosine kinase and their implications for the design of selective inhibitors. J Biol Chem, 279 (18): 18727-32. [PMID:14766749]

4. Burch JD, Barrett K, Chen Y, DeVoss J, Eigenbrot C, Goldsmith R, Ismaili MH, Lau K, Lin Z, Ortwine DF et al.. (2015) Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo. J Med Chem, 58 (9): 3806-16. [PMID:25844760]

5. Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR et al.. (2016) Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med, 374 (4): 323-32. [PMID:26641137]

6. Das J, Furch JA, Liu C, Moquin RV, Lin J, Spergel SH, McIntyre KW, Shuster DJ, O'Day KD, Penhallow B et al.. (2006) Discovery and SAR of 2-amino-5-(thioaryl)thiazoles as potent and selective Itk inhibitors. Bioorg Med Chem Lett, 16 (14): 3706-12. [PMID:16682193]

7. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

8. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

9. Hain A, Krämer M, Linka RM, Nakhaei-Rad S, Ahmadian MR, Häussinger D, Borkhardt A, Münk C. (2018) IL-2 Inducible Kinase ITK is Critical for HIV-1 Infection of Jurkat T-cells. Sci Rep, 8 (1): 3217. [PMID:29453458]

10. Herdemann M, Weber A, Jonveaux J, Schwoebel F, Stoeck M, Heit I. (2011) Optimisation of ITK inhibitors through successive iterative design cycles. Bioorg Med Chem Lett, 21 (6): 1852-6. [PMID:21316219]

11. Hodson R, Beausoleil AM. (2018) Compounds and methods for modulating interleukin-2-inducible t-cell kinase. Patent number: WO2018089261A2. Assignee: Corvus Pharmaceuticals, Inc.. Priority date: 03/11/2017. Publication date: 17/05/2018.

12. McLean LR, Zhang Y, Zaidi N, Bi X, Wang R, Dharanipragada R, Jurcak JG, Gillespy TA, Zhao Z, Musick KY et al.. (2012) X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase. Bioorg Med Chem Lett, 22 (9): 3296-300. [PMID:22464456]

13. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

14. Yao X, Sun X, Jin S, Yang L, Xu H, Rao Y. (2019) Discovery of 4-Aminoquinoline-3-carboxamide Derivatives as Potent Reversible Bruton's Tyrosine Kinase Inhibitors for the Treatment of Rheumatoid Arthritis. J Med Chem, 62 (14): 6561-6574. [PMID:31260299]

15. Zhong Y, Dong S, Strattan E, Ren L, Butchar JP, Thornton K, Mishra A, Porcu P, Bradshaw JM, Bisconte A et al.. (2015) Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694. J Biol Chem, 290 (10): 5960-78. [PMID:25593320]

16. Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R et al.. (2009) Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature, 462 (7276): 1070-4. [PMID:20033049]

How to cite this page

Tec family: IL2 inducible T cell kinase. Last modified on 26/02/2024. Accessed on 11/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2046.