TEK receptor tyrosine kinase | Type XII RTKs: TIE family of angiopoietin receptors | IUPHAR Guide to IMMUNOPHARMACOLOGY

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TEK receptor tyrosine kinase

  Target has curated data in GtoImmuPdb

Target id: 1842

Nomenclature: TEK receptor tyrosine kinase

Abbreviated Name: TIE2

Family: Type XII RTKs: TIE family of angiopoietin receptors

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1124 9p21 TEK TEK receptor tyrosine kinase
Mouse 1 1123 4 Tek TEK receptor tyrosine kinase
Rat - 1120 5q33 Tek TEK receptor tyrosine kinase
Previous and Unofficial Names
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
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
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
EC Number: 2.7.10.1
Natural/Endogenous Ligands
angiopoietin-1 {Sp: Human}
angiopoietin-4 {Sp: Human}

Download all structure-activity data for this target as a CSV file

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 Hs Inhibition 6.4 pKd 13
pKd 6.4 (Kd 3.7x10-7 M) [13]
pexmetinib Hs Inhibition 9.0 pIC50 3
pIC50 9.0 (IC50 1x10-9 M) [3]
compound 8h [PMID: 21561767] Hs Inhibition 8.7 pIC50 12
pIC50 8.7 (IC50 2.2x10-9 M) [12]
altiratinib Hs Inhibition 8.6 pIC50 5
pIC50 8.6 (IC50 2.4x10-9 M) [5]
merestinib 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 Hs Inhibition 7.6 pIC50 8
pIC50 7.6 (IC50 2.6x10-8 M) [8]
linifanib Hs Inhibition 6.8 pIC50 1
pIC50 6.8 (IC50 1.7x10-7 M) [1]
compound 5 [PMID: 17618114] Hs Inhibition 6.6 pIC50 10
pIC50 6.6 (IC50 2.5x10-7 M) [10]
compound 8i [PMID: 22765894] 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
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 Hs Inhibitor Inhibition 8.5 pKd
AST-487 Hs Inhibitor Inhibition 7.7 pKd
doramapimod Hs Inhibitor Inhibition 7.7 pKd
NVP-TAE684 Hs Inhibitor Inhibition 7.3 pKd
cediranib Hs Inhibitor Inhibition 6.8 pKd
staurosporine Hs Inhibitor Inhibition 6.8 pKd
crizotinib Hs Inhibitor Inhibition 6.6 pKd
PD-173955 Hs Inhibitor Inhibition 6.6 pKd
MLN-8054 Hs Inhibitor Inhibition 6.5 pKd
tamatinib 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
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 Hs Inhibitor Inhibition 4.3 75.0 20.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 5.1 -1.0 -2.0
staurosporine Hs Inhibitor Inhibition 22.0 2.0 -2.0
tozasertib Hs Inhibitor Inhibition 27.8
vandetanib Hs Inhibitor Inhibition 50.8
TWS119 Hs Inhibitor Inhibition 60.7 18.0 1.0
pazopanib Hs Inhibitor Inhibition 69.3
isogranulatimide Hs Inhibitor Inhibition 78.9 98.0 79.0
dovitinib Hs Inhibitor Inhibition 81.3
bosutinib 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].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0050728 negative regulation of inflammatory response TAS
GO:0050900 leukocyte migration TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0050728 negative regulation of inflammatory response TAS
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes
GO:0060216 definitive hemopoiesis TAS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0050900 leukocyte migration TAS
Clinically-Relevant Mutations and Pathophysiology
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]

How to cite this page

Type XII RTKs: TIE family of angiopoietin receptors: TEK receptor tyrosine kinase. Last modified on 24/04/2019. Accessed on 23/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1842.