Target Information
Target General Information | Top | |||||
---|---|---|---|---|---|---|
Target ID |
T92144
(Former ID: TTDC00161)
|
|||||
Target Name |
Angiopoietin 1 receptor (TEK)
|
|||||
Synonyms |
hTIE2; VMCM1; VMCM; Tyrosine-protein kinase receptor TIE-2; Tyrosine-protein kinase receptor TEK; Tyrosine kinase with Ig and EGF homology domains-2; Tunica interna endothelial cell kinase; TIE2; P140 TEK; Endothelial tyrosine kinase; Endothelial Cell-Specific Receptor TIE-2; CD202b antigen; CD202b
|
|||||
Gene Name |
TEK
|
|||||
Target Type |
Clinical trial target
|
[1] | ||||
Disease | [+] 6 Target-related Diseases | + | ||||
1 | Chronic arterial occlusive disease [ICD-11: BD4Z] | |||||
2 | Retinopathy [ICD-11: 9B71] | |||||
3 | Myeloproliferative neoplasm [ICD-11: 2A20] | |||||
4 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
5 | Mature B-cell lymphoma [ICD-11: 2A85] | |||||
6 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1. Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence.
Click to Show/Hide
|
|||||
BioChemical Class |
Kinase
|
|||||
UniProt ID | ||||||
EC Number |
EC 2.7.10.1
|
|||||
Sequence |
MDSLASLVLCGVSLLLSGTVEGAMDLILINSLPLVSDAETSLTCIASGWRPHEPITIGRD
FEALMNQHQDPLEVTQDVTREWAKKVVWKREKASKINGAYFCEGRVRGEAIRIRTMKMRQ QASFLPATLTMTVDKGDNVNISFKKVLIKEEDAVIYKNGSFIHSVPRHEVPDILEVHLPH AQPQDAGVYSARYIGGNLFTSAFTRLIVRRCEAQKWGPECNHLCTACMNNGVCHEDTGEC ICPPGFMGRTCEKACELHTFGRTCKERCSGQEGCKSYVFCLPDPYGCSCATGWKGLQCNE ACHPGFYGPDCKLRCSCNNGEMCDRFQGCLCSPGWQGLQCEREGIQRMTPKIVDLPDHIE VNSGKFNPICKASGWPLPTNEEMTLVKPDGTVLHPKDFNHTDHFSVAIFTIHRILPPDSG VWVCSVNTVAGMVEKPFNISVKVLPKPLNAPNVIDTGHNFAVINISSEPYFGDGPIKSKK LLYKPVNHYEAWQHIQVTNEIVTLNYLEPRTEYELCVQLVRRGEGGEGHPGPVRRFTTAS IGLPPPRGLNLLPKSQTTLNLTWQPIFPSSEDDFYVEVERRSVQKSDQQNIKVPGNLTSV LLNNLHPREQYVVRARVNTKAQGEWSEDLTAWTLSDILPPQPENIKISNITHSSAVISWT ILDGYSISSITIRYKVQGKNEDQHVDVKIKNATITQYQLKGLEPETAYQVDIFAENNIGS SNPAFSHELVTLPESQAPADLGGGKMLLIAILGSAGMTCLTVLLAFLIILQLKRANVQRR MAQAFQNVREEPAVQFNSGTLALNRKVKNNPDPTIYPVLDWNDIKFQDVIGEGNFGQVLK ARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELEVLCKLGHHPNIINLLGACEHRGYLYL AIEYAPHGNLLDFLRKSRVLETDPAFAIANSTASTLSSQQLLHFAADVARGMDYLSQKQF IHRDLAARNILVGENYVAKIADFGLSRGQEVYVKKTMGRLPVRWMAIESLNYSVYTTNSD VWSYGVLLWEIVSLGGTPYCGMTCAELYEKLPQGYRLEKPLNCDDEVYDLMRQCWREKPY ERPSFAQILVSLNRMLEERKTYVNTTLYEKFTYAGIDCSAEEAA Click to Show/Hide
|
|||||
3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T87DGB |
Drugs and Modes of Action | Top | |||||
---|---|---|---|---|---|---|
Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
1 | AKB-9778 | Drug Info | Phase 2 | Peripheral arterial disease | [2] | |
2 | DCC-2036 | Drug Info | Phase 1/2 | Chronic myeloid leukaemia | [3] | |
3 | Altiratinib | Drug Info | Phase 1 | Solid tumour/cancer | [4] | |
4 | CEP-11981 | Drug Info | Phase 1 | Solid tumour/cancer | [5], [6] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | ARRY-614 | Drug Info | Discontinued in Phase 1 | Myelodysplastic syndrome | [7] | |
Mode of Action | [+] 3 Modes of Action | + | ||||
Activator | [+] 2 Activator drugs | + | ||||
1 | AKB-9778 | Drug Info | [1] | |||
2 | ABTAA | Drug Info | [15] | |||
Inhibitor | [+] 9 Inhibitor drugs | + | ||||
1 | DCC-2036 | Drug Info | [8] | |||
2 | Altiratinib | Drug Info | [9] | |||
3 | (4-Phenoxy-phenyl)-quinazolin-4-yl-amine | Drug Info | [12] | |||
4 | 3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione | Drug Info | [13] | |||
5 | 3,4-diphenyl-1H-pyrrole-2,5-dione | Drug Info | [13] | |||
6 | 3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione | Drug Info | [13] | |||
7 | 3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione | Drug Info | [13] | |||
8 | A-420983 | Drug Info | [14] | |||
9 | PMID21561767C8h | Drug Info | [16] | |||
Modulator | [+] 3 Modulator drugs | + | ||||
1 | CEP-11981 | Drug Info | [10] | |||
2 | ARRY-614 | Drug Info | [11] | |||
3 | AP-101 | Drug Info | [10] |
Chemical Structure based Activity Landscape of Target | Top |
---|---|
Drug Property Profile of Target | Top | |
---|---|---|
(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
|
||
(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
|
||
(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
|
||
"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Co-Targets | Top | |||||
---|---|---|---|---|---|---|
Co-Targets |
Target Poor or Non Binders | Top | |||||
---|---|---|---|---|---|---|
Target Poor or Non Binders |
Target Regulators | Top | |||||
---|---|---|---|---|---|---|
Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
---|---|---|---|---|---|---|
Target Expression Profile (TEP) |
Target Affiliated Biological Pathways | Top | |||||
---|---|---|---|---|---|---|
KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
1 | Ras signaling pathway | |||||
2 | Rap1 signaling pathway | |||||
3 | HIF-1 signaling pathway | |||||
4 | PI3K-Akt signaling pathway | |||||
5 | Rheumatoid arthritis | |||||
NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
1 | Wnt Signaling Pathway | |||||
Panther Pathway | [+] 1 Panther Pathways | + | ||||
1 | Angiogenesis | |||||
PID Pathway | [+] 2 PID Pathways | + | ||||
1 | Angiopoietin receptor Tie2-mediated signaling | |||||
2 | SHP2 signaling | |||||
Reactome | [+] 2 Reactome Pathways | + | ||||
1 | Tie2 Signaling | |||||
2 | RAF/MAP kinase cascade | |||||
WikiPathways | [+] 3 WikiPathways | + | ||||
1 | Wnt Signaling Pathway Netpath | |||||
2 | Cell surface interactions at the vascular wall | |||||
3 | Angiogenesis |
Target-Related Models and Studies | Top | |||||
---|---|---|---|---|---|---|
Target Validation |
References | Top | |||||
---|---|---|---|---|---|---|
REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 2 | ClinicalTrials.gov (NCT02387788) Open Label Study to Assess the Efficacy and Safety of AKB-9778 in Subjects With Macular Edema Due to RVO. U.S. National Institutes of Health. | |||||
REF 3 | ClinicalTrials.gov (NCT00827138) Study Safety and Preliminary Efficacy of DCC-2036 in Patients With Leukemias (Ph+ CML With T315I Mutation). U.S. National Institutes of Health. | |||||
REF 4 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800040094) | |||||
REF 5 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8189). | |||||
REF 6 | ClinicalTrials.gov (NCT00875264) Open-Label Study to Determine the Maximum Tolerated Oral Dose of the Kinase Inhibitor CEP-11981 in Patients With Advanced Cancer. U.S. National Institutes of Health. | |||||
REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026289) | |||||
REF 8 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 9 | Clinical pipeline report, company report or official report of Deciphera Pharmaceuticals. | |||||
REF 10 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1842). | |||||
REF 11 | Cmpany report (Arraybiopharma) | |||||
REF 12 | Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck I. Bioorg Med Chem Lett. 2000 Oct 2;10(19):2167-70. | |||||
REF 13 | Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. J Med Chem. 2006 Feb 23;49(4):1271-81. | |||||
REF 14 | A-420983: a potent, orally active inhibitor of lck with efficacy in a model of transplant rejection. Bioorg Med Chem Lett. 2004 May 17;14(10):2613-6. | |||||
REF 15 | Amelioration of sepsis by TIE2 activation-induced vascular protection. Sci Transl Med. 2016 Apr 20;8(335):335ra55. | |||||
REF 16 | Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8. |
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.