General Information of Drug Therapeutic Target (DTT) (ID: TTDCBX5)

DTT Name Vascular endothelial growth factor receptor 3 (FLT-4)
Synonyms VEGFR3; VEGFR-3; VEGF-3 receptor; Tyrosine-protein kinase receptor FLT4; Fms-like tyrosine kinase 4
Gene Name FLT4
DTT Type
Successful target
[1]
BioChemical Class
Kinase
UniProt ID
VGFR3_HUMAN
TTD ID
T07303
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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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
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.
KEGG Pathway
Ras signaling pathway (hsa04014 )
Rap1 signaling pathway (hsa04015 )
Cytokine-cytokine receptor interaction (hsa04060 )
PI3K-Akt signaling pathway (hsa04151 )
Focal adhesion (hsa04510 )
Reactome Pathway
VEGF binds to VEGFR leading to receptor dimerization (R-HSA-195399 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
2 Approved Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Fruquintinib DMHOSCQ Colorectal cancer 2B91.Z Approved [2]
Tivozanib DMUKC5L Renal cell carcinoma 2C90 Approved [3]
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11 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
ABT-869 DMREDYP Solid tumour/cancer 2A00-2F9Z Phase 3 [4]
E-3810 DM42PFT Solid tumour/cancer 2A00-2F9Z Phase 3 [5]
PI-88 DMGZPX6 Hepatocellular carcinoma 2C12.02 Phase 3 [1]
Sulfatinib DMPOTM4 Neuroendocrine cancer 2B72.1 Phase 3 [6]
Taberminogene vadenovec DMW5PHL Vascular restinosis BE2Z Phase 3 [7]
MGCD516 DM752PU Solid tumour/cancer 2A00-2F9Z Phase 2/3 [8]
Famitinib DMSFWT7 Solid tumour/cancer 2A00-2F9Z Phase 2 [9]
VATALANIB DMY0UEQ Solid tumour/cancer 2A00-2F9Z Phase 2 [10]
MK-2461 DM21WBH Alzheimer disease 8A20 Phase 1/2 [11]
IMC-3C5 DMXI5ON Solid tumour/cancer 2A00-2F9Z Phase 1 [12]
JNJ-26483327 DMSQ3AZ Solid tumour/cancer 2A00-2F9Z Phase 1 [13]
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⏷ Show the Full List of 11 Clinical Trial Drug(s)
1 Patented Agent(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Pyrimidine derivative 15 DMV2Y84 N. A. N. A. Patented [14]
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20 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
(2-Methoxy-phenyl)-(5-phenyl-oxazol-2-yl)-amine DMQWD75 Discovery agent N.A. Investigative [10]
(5-Phenyl-oxazol-2-yl)-m-tolyl-amine DM1R5SF Discovery agent N.A. Investigative [10]
2-(5-Phenyl-oxazol-2-ylamino)-benzonitrile DMX6QMT Discovery agent N.A. Investigative [10]
3,6-Di-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine DMNV0EZ Discovery agent N.A. Investigative [15]
3-(5-Phenyl-oxazol-2-ylamino)-benzonitrile DMPBLM2 Discovery agent N.A. Investigative [10]
4-(5-Phenyl-oxazol-2-ylamino)-benzenesulfonamide DM3N9O5 Discovery agent N.A. Investigative [10]
4-Chloro-N-(2-chloro-benzoyl)-benzenesulfonamide DMVJ61A Discovery agent N.A. Investigative [16]
4-Chloro-N-(2-methyl-benzoyl)-benzenesulfonamide DM6SI78 Discovery agent N.A. Investigative [16]
4-Chloro-N-(3-chloro-benzoyl)-benzenesulfonamide DMI3OR9 Discovery agent N.A. Investigative [16]
4-Chloro-N-(4-chloro-benzoyl)-benzenesulfonamide DMTDX2S Discovery agent N.A. Investigative [16]
4-Chloro-N-(4-nitro-benzoyl)-benzenesulfonamide DMM0TL6 Discovery agent N.A. Investigative [16]
Anti-VEGFR 3 mab DMAJ6TC Discovery agent N.A. Investigative [8]
CB-676475 DMXON4L Discovery agent N.A. Investigative [17]
CEP-6331 DMNXBTD Discovery agent N.A. Investigative [18]
N-(2,4-Dichloro-benzoyl)-benzenesulfonamide DMHI4Y6 Discovery agent N.A. Investigative [16]
N-(3-Bromo-benzoyl)-4-chloro-benzenesulfonamide DMOQ08F Discovery agent N.A. Investigative [16]
Phenyl-(5-phenyl-oxazol-2-yl)-amine DMR2B4O Discovery agent N.A. Investigative [10]
PMID22765894C8h DMH5RFU Discovery agent N.A. Investigative [19]
SAR-131675 DMSYE4W Solid tumour/cancer 2A00-2F9Z Investigative [8]
[3-(5-Phenyl-oxazol-2-ylamino)-phenyl]-methanol DMD0LCU Discovery agent N.A. Investigative [10]
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⏷ Show the Full List of 20 Investigative Drug(s)

Molecular Expression Atlas (MEA) of This DTT

Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This DTT
Disease Name ICD 11 Studied Tissue p-value Fold-Change Z-score
Alzheimer's disease 8A00.0 Entorhinal cortex 6.00E-01 -0.04 -0.23
Prostate cancer 2C82 Prostate 8.36E-03 0.45 0.97
Lung cancer 2C82 Lung tissue 4.66E-60 -0.64 -1.74
Rectal cancer 2C82 Rectal colon tissue 3.75E-02 0.12 1.23
Renal cancer 2C82 Kidney 7.15E-01 -0.17 -0.69
Myelodysplastic syndrome 2C82 Bone marrow 9.59E-01 -0.06 -0.41
Breast cancer 2C82 Breast tissue 1.41E-35 -0.31 -0.93
Acute myelocytic leukaemia 2C82 Bone marrow 7.70E-03 0.02 0.12
Head and neck cancer 2C82 Head and neck tissue 1.14E-01 0.04 0.17
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⏷ Show the Full List of DTT Expression Under 9 Diseases

References

1 Company report (Medigen)
2 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.
3 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services
4 Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2006 Apr;5(4):995-1006.
5 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.
6 Clinical pipeline report, company report or official report of Hutchison Medi Pharma.
7 Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol Sci. 2014 Nov;35(11):604-20.
8 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).
9 Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 2013 Apr;168(7):1687-706.
10 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.
11 MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
12 Bevacizumab and breast cancer: what does the future hold . Future Oncol. 2012 April; 8(4): 403-414.
13 National Cancer Institute Drug Dictionary (drug id 596693).
14 VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016).Expert Opin Ther Pat. 2017 Sep;27(9):987-1004.
15 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.
16 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.
17 Synthesis of a novel biotin-tagged photoaffinity probe for VEGF receptor tyrosine kinases. Bioorg Med Chem Lett. 2006 Jan 1;16(1):129-33.
18 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.
19 The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85.