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TEK receptor tyrosine kinase

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Target id: 1842

Nomenclature: TEK receptor tyrosine kinase

Abbreviated Name: TIE2

Family: Type XII RTKs: TIE family of angiopoietin receptors

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1124 9p21.2 TEK TEK receptor tyrosine kinase
Mouse 1 1122 4 43.34 cM Tek TEK receptor tyrosine kinase
Rat - 1120 5q33 Tek TEK receptor tyrosine kinase
Previous and Unofficial Names Click here for help
angiopoietin-1 receptor | CD202b | Hyk | TEK tyrosine kinase, endothelial | tyrosine kinases that contain immunoglobulin-like loops and epidermal growth factor-similar domains 2 | venous malformations, multiple cutaneous and mucosal | VMCM | VMCM1
Database Links Click here for help
Alphafold Q02763 (Hs), Q02858 (Mm)
BRENDA 2.7.10.1
CATH/Gene3D 2.60.40.10
ChEMBL Target CHEMBL4128 (Hs), CHEMBL5199 (Mm)
DrugBank Target Q02763 (Hs)
Ensembl Gene ENSG00000120156 (Hs), ENSMUSG00000006386 (Mm), ENSRNOG00000008587 (Rn)
Entrez Gene 7010 (Hs), 21687 (Mm), 89804 (Rn)
Human Protein Atlas ENSG00000120156 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:7010 (Hs), mmu:21687 (Mm), rno:89804 (Rn)
OMIM 600221 (Hs)
Orphanet ORPHA120020 (Hs)
Pharos Q02763 (Hs)
RefSeq Nucleotide NM_000459 (Hs), NM_013690 (Mm), NM_001105737 (Rn)
RefSeq Protein NP_000450 (Hs), NP_038718 (Mm), NP_001099207 (Rn)
UniProtKB Q02763 (Hs), Q02858 (Mm)
Wikipedia TEK (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail.
PDB Id:  1FVR
Resolution:  2.2Å
Species:  Human
References:  11
Image of receptor 3D structure from RCSB PDB
Description:  Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors.
PDB Id:  2OO8
Resolution:  2.2Å
Species:  Human
References:  7
Enzyme Reaction Click here for help
EC Number: 2.7.10.1
Natural/Endogenous Ligands Click here for help
angiopoietin-1 {Sp: Human}
angiopoietin-4 {Sp: Human}

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
DDR1/2 inhibitor 5n Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.4 pKd 13
⤷ pKd 6.4 (Kd 3.7x10-7 M) [13]
pexmetinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.0 pIC50 3
⤷ pIC50 9.0 (IC50 1x10-9 M) [3]
compound 8h [PMID: 21561767] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.7 pIC50 12
⤷ pIC50 8.7 (IC50 2.2x10-9 M) [12]
altiratinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Guide to Malaria Pharmacology Ligand Hs Inhibition 8.6 pIC50 5
⤷ pIC50 8.6 (IC50 2.4x10-9 M) [5]
merestinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.4 pIC50 15
⤷ pIC50 8.4 (IC50 4x10-9 M) [15]
Description: Inhibition of in vitro biochemical activity by EMD Millipore assay.
CEP-11981 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 8
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [8]
linifanib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.8 pIC50 1
⤷ pIC50 6.8 (IC50 1.7x10-7 M) [1]
compound 5 [PMID: 17618114] Small molecule or natural product Hs Inhibition 6.6 pIC50 10
⤷ pIC50 6.6 (IC50 2.5x10-7 M) [10]
compound 8i [PMID: 22765894] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.6 pIC50 16
⤷ pIC50 6.6 (IC50 2.7x10-7 M) [16]
Agonist Comments
Under pathogen-free conditions angiopoietin-2 (ANG2) behaves as a TIE2 agonist, whereas it acts as a TIE2 antagonist during Mycoplasma pulmonis infection [9]
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: 4,14
Key to terms and symbols Click column headers to sort
Target used in screen: TIE2
Ligand Sp. Type Action Value Parameter
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.5 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 7.7 pKd
doramapimod Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.7 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.3 pKd
cediranib Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.6 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
MLN-8054 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
axitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 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: 2,6
Key to terms and symbols Click column headers to sort
Target used in screen: Tie2/TIE2(TEK)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 4.3 75.0 20.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.1 -1.0 -2.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 22.0 2.0 -2.0
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 27.8
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 50.8
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 60.7 18.0 1.0
pazopanib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 69.3
isogranulatimide Small molecule or natural product Hs Inhibitor Inhibition 78.9 98.0 79.0
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 81.3
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 82.6
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
In inflammation, angiopoietin-2 (ANG2) antagonism of TIE2 initiates a positive feedback loop via forkhead box O1 (FOXO1) activation, which drives further ANG2 expression and enhances vascular remodeling and leakage [9].
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Venous malformations, multiple cutaneous and mucosal
Synonyms: Mucocutaneous venous malformations [Orphanet: ORPHA2451]
OMIM: 600195
Orphanet: ORPHA2451

References

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1. Albert DH, Tapang P, Magoc TJ, Pease LJ, Reuter DR, Wei RQ, Li J, Guo J, Bousquet PF, Ghoreishi-Haack NS et al.. (2006) Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther, 5 (4): 995-1006. [PMID:16648571]

2. 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]

3. Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, Giricz O, Sukrithan V, Nwankwo G, Shahnaz S et al.. (2016) Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res, 76 (16): 4841-4849. [PMID:27287719]

4. 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]

5. Flynn DL, Kaufman MD, Smith BD. (2016) Inhibition of tumor cell interactions with the microenvironment resulting in a reduction in tumor growth and disease progression. Patent number: WO2016061231. Assignee: Deciphera Pharmaceuticals, Llc. Priority date: 14/10/2014. Publication date: 21/04/2016.

6. 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]

7. Hodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Caenepeel S, Cee VJ, Chaffee SC, Emery M, Fretland J et al.. (2007) Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors. Bioorg Med Chem Lett, 17 (10): 2886-9. [PMID:17350837]

8. Hudkins RL, Becknell NC, Zulli AL, Underiner TL, Angeles TS, Aimone LD, Albom MS, Chang H, Miknyoczki SJ, Hunter K et al.. (2012) Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent. J Med Chem, 55 (2): 903-13. [PMID:22148921]

9. Kim M, Allen B, Korhonen EA, Nitschké M, Yang HW, Baluk P, Saharinen P, Alitalo K, Daly C, Thurston G et al.. (2016) Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation. J Clin Invest, 126 (9): 3511-25. [PMID:27548529]

10. Semones M, Feng Y, Johnson N, Adams JL, Winkler J, Hansbury M. (2007) Pyridinylimidazole inhibitors of Tie2 kinase. Bioorg Med Chem Lett, 17 (17): 4756-60. [PMID:17618114]

11. Shewchuk LM, Hassell AM, Ellis B, Holmes WD, Davis R, Horne EL, Kadwell SH, McKee DD, Moore JT. (2000) Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail. Structure, 8 (11): 1105-13. [PMID:11080633]

12. Thomas M, Huang WS, Wen D, Zhu X, Wang Y, Metcalf CA, Liu S, Chen I, Romero J, Zou D et al.. (2011) Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett, 21 (12): 3743-8. [PMID:21561767]

13. Wang Z, Zhang Y, Pinkas DM, Fox AE, Luo J, Huang H, Cui S, Xiang Q, Xu T, Xun Q et al.. (2018) Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2. J Med Chem, 61 (17): 7977-7990. [PMID:30075624]

14. 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]

15. Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek BW, Manro JR et al.. (2013) LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs, 31 (4): 833-44. [PMID:23275061]

16. You WK, Sennino B, Williamson CW, Falcón B, Hashizume H, Yao LC, Aftab DT, McDonald DM. (2011) VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res, 71 (14): 4758-68. [PMID:21613405]

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