Target General Infomation
Target ID
T07303
Former ID
TTDC00290
Target Name
Vascular endothelial growth factor receptor 3
Gene Name
FLT4
Synonyms
VEGFR-3; VEGFR3; Fms-like tyrosine kinase 4; FLT-4; Tyrosine-protein kinase receptor FLT4; VEGF-3 receptor; FLT4
Target Type
Successful
Disease Alzheimer disease [ICD9: 331; ICD10: G30]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hepatocellular carcinoma [ICD9: 155; ICD10: C22.0]
Prostate cancer; Lung cancer [ICD9: 140-229, 162, 185; ICD10: C33-C34, C61]
Renal cancer [ICD9: 140-229, 189; ICD10: C64]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Vascular restinosis following vascular graft surgery [ICD10: T82.858A]
Function
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. 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. Mediatesphosphorylation 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'.
BioChemical Class
Kinase
Target Validation
T07303
UniProt ID
EC Number
EC 2.7.10.1
Sequence
MQRGAALCLRLWLCLGLLDGLVSGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWA
WPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARI
EGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDG
QEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSL
ELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNV
SQHDLGSYVCKANNGIQRFRESTEVIVHENPFISVEWLKGPILEATAGDELVKLPVKLAA
YPPPEFQWYKDGKALSGRHSPHALVLKEVTEASTGTYTLALWNSAAGLRRNISLELVVNV
PPQIHEKEASSPSIYSRHSRQALTCTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQQ
DLMPQCRDWRAVTTQDAVNPIESLDTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKV
GQDERLIYFYVTTIPDGFTIESKPSEELLEGQPVLLSCQADSYKYEHLRWYRLNLSTLHD
AHGNPLLLDCKNVHLFATPLAASLEEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRS
HDKHCHKKYLSVQALEAPRLTQNLTDLLVNVSDSLEMQCLVAGAHAPSIVWYKDERLLEE
KSGVDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNSSASVAVEGSEDKGSMEIVILV
GTGVIAVFFWVLLLLIFCNMRRPAHADIKTGYLSIIMDPGEVPLEEQCEYLSYDASQWEF
PRERLHLGRVLGYGAFGKVVEASAFGIHKGSSCDTVAVKMLKEGATASEHRALMSELKIL
IHIGNHLNVVNLLGACTKPQGPLMVIVEFCKYGNLSNFLRAKRDAFSPCAEKSPEQRGRF
RAMVELARLDRRRPGSSDRVLFARFSKTEGGARRASPDQEAEDLWLSPLTMEDLVCYSFQ
VARGMEFLASRKCIHRDLAARNILLSESDVVKICDFGLARDIYKDPDYVRKGSARLPLKW
MAPESIFDKVYTTQSDVWSFGVLLWEIFSLGASPYPGVQINEEFCQRLRDGTRMRAPELA
TPAIRRIMLNCWSGDPKARPAFSELVEILGDLLQGRGLQEEEEVCMAPRSSQSSEEGSFS
QVSTMALHIAQADAEDSPPSLQRHSLAARYYNWVSFPGCLARGAETRGSSRMKTFEEFPM
TPTTYKGSVDNQTDSGMVLASEEFEQIESRHRQESGFSCKGPGQNVAVTRAHPDSQGRRR
RPERGARGGQVFYNSEYGELSEPSEEDHCSPSARVTFFTDNSY
Drugs and Mode of Action
Drug(s) ABT-869 Drug Info Phase 3 Solid tumours [528171], [528172], [541001]
E-3810 Drug Info Phase 3 Solid tumours [524749], [542632]
Fruquintinib Drug Info Phase 3 Cancer [525024]
PI-88 Drug Info Phase 3 Hepatocellular carcinoma [537114]
Taberminogene vadenovec Drug Info Phase 3 Vascular restinosis following vascular graft surgery [522657]
Tivozanib Drug Info Phase 3 Renal cancer [522960], [541307]
Famitinib Drug Info Phase 2 Cancer [532104], [542811]
PI-88 Drug Info Phase 2 Prostate cancer; Lung cancer [537114]
VATALANIB Drug Info Phase 2 Solid tumours [521851], [541046]
MK-2461 Drug Info Phase 1/2 Alzheimer disease [530708]
IMC-3C5 Drug Info Phase 1 Solid tumours [523345]
JNJ-26483327 Drug Info Phase 1 Cancer [522319]
Sulfatinib Drug Info Phase 1 Cancer [524745]
VEGFR3 Monoclonal Antibody Drug Info Phase 1 Cancer [549713]
Inhibitor (2-Methoxy-phenyl)-(5-phenyl-oxazol-2-yl)-amine Drug Info [527458]
(5-Phenyl-oxazol-2-yl)-m-tolyl-amine Drug Info [527458]
2-(5-Phenyl-oxazol-2-ylamino)-benzonitrile Drug Info [527458]
3,6-Di-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine Drug Info [526421]
3-(5-Phenyl-oxazol-2-ylamino)-benzonitrile Drug Info [527458]
4-(5-Phenyl-oxazol-2-ylamino)-benzenesulfonamide Drug Info [527458]
4-Chloro-N-(2-chloro-benzoyl)-benzenesulfonamide Drug Info [527245]
4-Chloro-N-(2-methyl-benzoyl)-benzenesulfonamide Drug Info [527245]
4-Chloro-N-(3-chloro-benzoyl)-benzenesulfonamide Drug Info [527245]
4-Chloro-N-(4-chloro-benzoyl)-benzenesulfonamide Drug Info [527245]
4-Chloro-N-(4-nitro-benzoyl)-benzenesulfonamide Drug Info [527245]
Anti-VEGFR 3 mab Drug Info [543500]
CB-676475 Drug Info [527794]
CEP-6331 Drug Info [529647]
compound 8h Drug Info [531959]
E-3810 Drug Info [525382]
Famitinib Drug Info [532104]
Fruquintinib Drug Info [533061]
JNJ-26483327 Drug Info [550422]
MG-516 Drug Info [543500]
MK-2461 Drug Info [530708]
N-(2,4-Dichloro-benzoyl)-benzenesulfonamide Drug Info [527245]
N-(3-Bromo-benzoyl)-4-chloro-benzenesulfonamide Drug Info [527245]
Phenyl-(5-phenyl-oxazol-2-yl)-amine Drug Info [527458]
SAR-131675 Drug Info [543500]
Sulfatinib Drug Info [550989]
VATALANIB Drug Info [527458]
[3-(5-Phenyl-oxazol-2-ylamino)-phenyl]-methanol Drug Info [527458]
Modulator ABT-869 Drug Info [528171], [549798]
IMC-3C5 Drug Info [544262]
PI-88 Drug Info
Taberminogene vadenovec Drug Info [532990]
Tivozanib Drug Info [550325]
VEGFR3 Monoclonal Antibody Drug Info [543500]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Ras signaling pathway
Rap1 signaling pathway
Cytokine-cytokine receptor interaction
PI3K-Akt signaling pathway
Focal adhesion
NetPath Pathway TNFalpha Signaling Pathway
Pathway Interaction Database VEGF and VEGFR signaling network
VEGFR3 signaling in lymphatic endothelium
Reactome VEGF binds to VEGFR leading to receptor dimerization
WikiPathways Signaling by VEGF
References
Ref 521851ClinicalTrials.gov (NCT00348790) Vatalanib in Treating Patients With Recurrent or Progressive Meningioma. U.S. National Institutes of Health.
Ref 522319ClinicalTrials.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 522657ClinicalTrials.gov (NCT00895479) Adenovirus Vascular Endothelial Growth Factor (VEGF) Therapy in Vascular Access - Novel Trinam AGainst Control Evidence. U.S. National Institutes of Health.
Ref 522960ClinicalTrials.gov (NCT01076010) An Extension Treatment Protocol for Subjects Who Have Participated in a Phase 3 Study of Tivozanib Versus Sorafenib in Renal Cell Carcinoma (Protocol AV-951-09-301). U.S. National Institutes of Health.
Ref 523345ClinicalTrials.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 524745ClinicalTrials.gov (NCT02133157) Phase I Study of Sulfatinib(HMPL-012) in Patients With Advanced Solid Tumors. U.S. National Institutes of Health.
Ref 524749ClinicalTrials.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 525024ClinicalTrials.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 528171Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006 Apr;5(4):995-1006.
Ref 528172Inhibition 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 530708MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
Ref 532104Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
Ref 537114Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
Ref 541001(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 541046(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 541307(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: 6058).
Ref 542632(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 542811(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 549713J Clin Oncol 29: 2011 (suppl, abstr TPS150).
Ref 525382E-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. doi: 10.1158/0008-5472.CAN-10-2700. Epub 2011 Jan 6.
Ref 526421Bioorg Med Chem Lett. 2002 Oct 7;12(19):2767-70.Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors.
Ref 527245J Med Chem. 2004 Oct 21;47(22):5367-80.Acyl sulfonamide anti-proliferatives: benzene substituent structure-activity relationships for a novel class of antitumor agents.
Ref 527458J Med Chem. 2005 Mar 10;48(5):1610-9.Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors.
Ref 527794Bioorg Med Chem Lett. 2006 Jan 1;16(1):129-33. Epub 2005 Oct 10.Synthesis of a novel biotin-tagged photoaffinity probe for VEGF receptor tyrosine kinases.
Ref 528171Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006 Apr;5(4):995-1006.
Ref 529647J Med Chem. 2008 Sep 25;51(18):5680-9. Epub 2008 Aug 21.Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.
Ref 530708MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
Ref 531959The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.
Ref 532104Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
Ref 532990Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol Sci. 2014 Nov;35(11):604-20.
Ref 533061Discovery 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 543500(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 544262Bevacizumab and breast cancer: what does the future hold?. Future Oncol. 2012 April; 8(4): 403-414.
Ref 549798Inhibition 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 550325Clinical pipeline report, company report or official report of AVEO Pharmaceuticals.
Ref 550422National Cancer Institute Drug Dictionary (drug id 596693).
Ref 550989Clinical pipeline report, company report or official report of Hutchison Medi Pharma.

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