Target Information
Target General Infomation | |||||
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Target ID |
T07303
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Former ID |
TTDC00290
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Target Name |
Vascular endothelial growth factor receptor 3
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Gene Name |
FLT4
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Synonyms |
VEGFR-3; VEGFR3; Fms-like tyrosine kinase 4; FLT-4; Tyrosine-protein kinase receptor FLT4; VEGF-3 receptor; FLT4
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Target Type |
Successful
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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'.
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BioChemical Class |
Kinase
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Target Validation |
T07303
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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 |
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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 521851 | ClinicalTrials.gov (NCT00348790) Vatalanib in Treating Patients With Recurrent or Progressive Meningioma. U.S. National Institutes of Health. | ||||
Ref 522319 | 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 522657 | 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 522960 | ClinicalTrials.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 523345 | 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 524745 | ClinicalTrials.gov (NCT02133157) Phase I Study of Sulfatinib(HMPL-012) in Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | ||||
Ref 524749 | 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 525024 | 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 528171 | Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006 Apr;5(4):995-1006. | ||||
Ref 528172 | 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 530708 | MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33. | ||||
Ref 532104 | 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 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 525382 | 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. doi: 10.1158/0008-5472.CAN-10-2700. Epub 2011 Jan 6. | ||||
Ref 526421 | Bioorg 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 527245 | J 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 527458 | J 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 527794 | Bioorg 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 528171 | Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006 Apr;5(4):995-1006. | ||||
Ref 529647 | J 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 530708 | MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33. | ||||
Ref 531959 | The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85. | ||||
Ref 532104 | 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 532990 | Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol Sci. 2014 Nov;35(11):604-20. | ||||
Ref 533061 | 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 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 544262 | Bevacizumab and breast cancer: what does the future hold?. Future Oncol. 2012 April; 8(4): 403-414. |
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