Target Information
| Target General Information | Top | |||||
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| Target ID |
T07303
(Former ID: TTDC00290)
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| Target Name |
Vascular endothelial growth factor receptor 3 (FLT-4)
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| Synonyms |
VEGFR3; VEGFR-3; VEGF-3 receptor; Tyrosine-protein kinase receptor FLT4; Fms-like tyrosine kinase 4
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| Gene Name |
FLT4
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Renal cell carcinoma [ICD-11: 2C90] | |||||
| Function |
Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'. Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.10.1
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| Sequence |
MQRGAALCLRLWLCLGLLDGLVSGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWA
WPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARI EGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDG QEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSL ELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNV SQHDLGSYVCKANNGIQRFRESTEVIVHENPFISVEWLKGPILEATAGDELVKLPVKLAA YPPPEFQWYKDGKALSGRHSPHALVLKEVTEASTGTYTLALWNSAAGLRRNISLELVVNV PPQIHEKEASSPSIYSRHSRQALTCTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQQ DLMPQCRDWRAVTTQDAVNPIESLDTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKV GQDERLIYFYVTTIPDGFTIESKPSEELLEGQPVLLSCQADSYKYEHLRWYRLNLSTLHD AHGNPLLLDCKNVHLFATPLAASLEEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRS HDKHCHKKYLSVQALEAPRLTQNLTDLLVNVSDSLEMQCLVAGAHAPSIVWYKDERLLEE KSGVDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNSSASVAVEGSEDKGSMEIVILV GTGVIAVFFWVLLLLIFCNMRRPAHADIKTGYLSIIMDPGEVPLEEQCEYLSYDASQWEF PRERLHLGRVLGYGAFGKVVEASAFGIHKGSSCDTVAVKMLKEGATASEHRALMSELKIL IHIGNHLNVVNLLGACTKPQGPLMVIVEFCKYGNLSNFLRAKRDAFSPCAEKSPEQRGRF RAMVELARLDRRRPGSSDRVLFARFSKTEGGARRASPDQEAEDLWLSPLTMEDLVCYSFQ VARGMEFLASRKCIHRDLAARNILLSESDVVKICDFGLARDIYKDPDYVRKGSARLPLKW MAPESIFDKVYTTQSDVWSFGVLLWEIFSLGASPYPGVQINEEFCQRLRDGTRMRAPELA TPAIRRIMLNCWSGDPKARPAFSELVEILGDLLQGRGLQEEEEVCMAPRSSQSSEEGSFS QVSTMALHIAQADAEDSPPSLQRHSLAARYYNWVSFPGCLARGAETRGSSRMKTFEEFPM TPTTYKGSVDNQTDSGMVLASEEFEQIESRHRQESGFSCKGPGQNVAVTRAHPDSQGRRR RPERGARGGQVFYNSEYGELSEPSEEDHCSPSARVTFFTDNSY Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T29JZ3 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Tivozanib | Drug Info | Approved | Renal cell carcinoma | [2] | |
| Clinical Trial Drug(s) | [+] 12 Clinical Trial Drugs | + | ||||
| 1 | ABT-869 | Drug Info | Phase 3 | Solid tumour/cancer | [3], [4], [5] | |
| 2 | E-3810 | Drug Info | Phase 3 | Solid tumour/cancer | [6], [7] | |
| 3 | Fruquintinib | Drug Info | Phase 3 | Solid tumour/cancer | [8] | |
| 4 | PI-88 | Drug Info | Phase 3 | Hepatocellular carcinoma | [9] | |
| 5 | Sulfatinib | Drug Info | Phase 3 | Neuroendocrine cancer | [10] | |
| 6 | Taberminogene vadenovec | Drug Info | Phase 3 | Vascular restinosis | [11] | |
| 7 | MGCD516 | Drug Info | Phase 2/3 | Solid tumour/cancer | [12] | |
| 8 | Famitinib | Drug Info | Phase 2 | Solid tumour/cancer | [13], [14] | |
| 9 | VATALANIB | Drug Info | Phase 2 | Solid tumour/cancer | [15], [16] | |
| 10 | MK-2461 | Drug Info | Phase 1/2 | Alzheimer disease | [17] | |
| 11 | IMC-3C5 | Drug Info | Phase 1 | Solid tumour/cancer | [18] | |
| 12 | JNJ-26483327 | Drug Info | Phase 1 | Solid tumour/cancer | [19] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 5 Modulator drugs | + | ||||
| 1 | Tivozanib | Drug Info | [2] | |||
| 2 | ABT-869 | Drug Info | [4], [20] | |||
| 3 | PI-88 | Drug Info | [1] | |||
| 4 | Taberminogene vadenovec | Drug Info | [24] | |||
| 5 | IMC-3C5 | Drug Info | [27] | |||
| Inhibitor | [+] 29 Inhibitor drugs | + | ||||
| 1 | E-3810 | Drug Info | [21] | |||
| 2 | Fruquintinib | Drug Info | [22] | |||
| 3 | Sulfatinib | Drug Info | [23] | |||
| 4 | MGCD516 | Drug Info | [25] | |||
| 5 | Famitinib | Drug Info | [14] | |||
| 6 | VATALANIB | Drug Info | [26] | |||
| 7 | MK-2461 | Drug Info | [17] | |||
| 8 | JNJ-26483327 | Drug Info | [28] | |||
| 9 | Pyrimidine derivative 15 | Drug Info | [29] | |||
| 10 | (2-Methoxy-phenyl)-(5-phenyl-oxazol-2-yl)-amine | Drug Info | [26] | |||
| 11 | (5-Phenyl-oxazol-2-yl)-m-tolyl-amine | Drug Info | [26] | |||
| 12 | 2-(5-Phenyl-oxazol-2-ylamino)-benzonitrile | Drug Info | [26] | |||
| 13 | 3,6-Di-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine | Drug Info | [30] | |||
| 14 | 3-(5-Phenyl-oxazol-2-ylamino)-benzonitrile | Drug Info | [26] | |||
| 15 | 4-(5-Phenyl-oxazol-2-ylamino)-benzenesulfonamide | Drug Info | [26] | |||
| 16 | 4-Chloro-N-(2-chloro-benzoyl)-benzenesulfonamide | Drug Info | [31] | |||
| 17 | 4-Chloro-N-(2-methyl-benzoyl)-benzenesulfonamide | Drug Info | [31] | |||
| 18 | 4-Chloro-N-(3-chloro-benzoyl)-benzenesulfonamide | Drug Info | [31] | |||
| 19 | 4-Chloro-N-(4-chloro-benzoyl)-benzenesulfonamide | Drug Info | [31] | |||
| 20 | 4-Chloro-N-(4-nitro-benzoyl)-benzenesulfonamide | Drug Info | [31] | |||
| 21 | Anti-VEGFR 3 mab | Drug Info | [25] | |||
| 22 | CB-676475 | Drug Info | [32] | |||
| 23 | CEP-6331 | Drug Info | [33] | |||
| 24 | N-(2,4-Dichloro-benzoyl)-benzenesulfonamide | Drug Info | [31] | |||
| 25 | N-(3-Bromo-benzoyl)-4-chloro-benzenesulfonamide | Drug Info | [31] | |||
| 26 | Phenyl-(5-phenyl-oxazol-2-yl)-amine | Drug Info | [26] | |||
| 27 | PMID22765894C8h | Drug Info | [34] | |||
| 28 | SAR-131675 | Drug Info | [25] | |||
| 29 | [3-(5-Phenyl-oxazol-2-ylamino)-phenyl]-methanol | Drug Info | [26] | |||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | |||||
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| KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
| 1 | Ras signaling pathway | |||||
| 2 | Rap1 signaling pathway | |||||
| 3 | Cytokine-cytokine receptor interaction | |||||
| 4 | PI3K-Akt signaling pathway | |||||
| 5 | Focal adhesion | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TNFalpha Signaling Pathway | |||||
| PID Pathway | [+] 2 PID Pathways | + | ||||
| 1 | VEGF and VEGFR signaling network | |||||
| 2 | VEGFR3 signaling in lymphatic endothelium | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | VEGF binds to VEGFR leading to receptor dimerization | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Signaling by VEGF | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Company report (Medigen) | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services | |||||
| REF 3 | 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: 5657). | |||||
| REF 4 | Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006 Apr;5(4):995-1006. | |||||
| REF 5 | Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. | |||||
| REF 6 | 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: 7649). | |||||
| REF 7 | ClinicalTrials.gov (NCT02135107) A Double-blind Comparative Study of the Efficacy and Safety of E3810 10mg Once and Twice Daily in Maintenance Therapy for PPI Resistant Gastroesophageal Reflux Disease Patients. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT02314819) A Phase III Trial Evaluating Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients RESCO). U.S. National Institutes of Health. | |||||
| REF 9 | Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127. | |||||
| REF 10 | ClinicalTrials.gov (NCT02589821) Phase III Study of Surufatinib in Treating Advanced Pancreatic Neuroendocrine Tumors. U.S. National Institutes of Health. | |||||
| REF 11 | ClinicalTrials.gov (NCT00895479) Adenovirus Vascular Endothelial Growth Factor (VEGF) Therapy in Vascular Access - Novel Trinam AGainst Control Evidence. U.S. National Institutes of Health. | |||||
| REF 12 | ClinicalTrials.gov (NCT04887870) Study of Sitravatinib With or Without Other Anticancer Therapies Receiving Clinical Benefit From Parent Study. U.S. National Institutes of Health. | |||||
| REF 13 | 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: 7886). | |||||
| REF 14 | Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706. | |||||
| REF 15 | 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: 5705). | |||||
| REF 16 | ClinicalTrials.gov (NCT00348790) Vatalanib in Treating Patients With Recurrent or Progressive Meningioma. U.S. National Institutes of Health. | |||||
| REF 17 | MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33. | |||||
| REF 18 | ClinicalTrials.gov (NCT01288989) A Study of Anti-VEGFR-3 Monoclonal Antibody IMC-3C5 in Subjects With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 19 | ClinicalTrials.gov (NCT00676299) A Safety and Dose-finding Study of JNJ-26483327, a Drug in Development for Cancer, for Patients With Advanced and/or Refractory Solid Malignancies.. U.S. National Institutes of Health. | |||||
| REF 20 | Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. | |||||
| REF 21 | E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011 Feb 15;71(4):1396-405. | |||||
| REF 22 | Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther. 2014;15(12):1635-45. | |||||
| REF 23 | Clinical pipeline report, company report or official report of Hutchison Medi Pharma. | |||||
| REF 24 | Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol Sci. 2014 Nov;35(11):604-20. | |||||
| REF 25 | 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: 1814). | |||||
| REF 26 | Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors. J Med Chem. 2005 Mar 10;48(5):1610-9. | |||||
| REF 27 | Bevacizumab and breast cancer: what does the future hold . Future Oncol. 2012 April; 8(4): 403-414. | |||||
| REF 28 | National Cancer Institute Drug Dictionary (drug id 596693). | |||||
| REF 29 | VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016).Expert Opin Ther Pat. 2017 Sep;27(9):987-1004. | |||||
| REF 30 | Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors. Bioorg Med Chem Lett. 2002 Oct 7;12(19):2767-70. | |||||
| REF 31 | Acyl sulfonamide anti-proliferatives: benzene substituent structure-activity relationships for a novel class of antitumor agents. J Med Chem. 2004 Oct 21;47(22):5367-80. | |||||
| REF 32 | Synthesis of a novel biotin-tagged photoaffinity probe for VEGF receptor tyrosine kinases. Bioorg Med Chem Lett. 2006 Jan 1;16(1):129-33. | |||||
| REF 33 | Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-linea... J Med Chem. 2008 Sep 25;51(18):5680-9. | |||||
| REF 34 | The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85. | |||||
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