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fms related receptor tyrosine kinase 4

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Target not currently curated in GtoImmuPdb

Target id: 1814

Nomenclature: fms related receptor tyrosine kinase 4

Abbreviated Name: VEGFR-3

Family: Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1363 5q35.3 FLT4 fms related receptor tyrosine kinase 4
Mouse 1 1363 11 29.69 cM Flt4 FMS-like tyrosine kinase 4
Rat 1 1363 10q21 Flt4 Fms related receptor tyrosine kinase 4
Previous and Unofficial Names Click here for help
fms related tyrosine kinase 4 | PCL | vascular endothelial growth factor receptor 3
Database Links Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction Click here for help
EC Number: 2.7.10.1
Natural/Endogenous Ligands Click here for help
VEGFC {Sp: Human}
VEGFD {Sp: Human}
VEGFE {Sp: Human}

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
tivozanib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.6 pIC50 17
pIC50 9.6 (IC50 2.4x10-10 M) [17]
fruquintinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 9.3 pIC50 21
pIC50 9.3 (IC50 5x10-10 M) [21]
Description: Evaluated in a [32]p-ATP incorporation assay
catequentinib Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 9.0 pIC50 4
pIC50 9.0 (IC50 1x10-9 M) [4]
Description: In vitro activity
sitravatinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.7 pIC50 19
pIC50 8.7 (IC50 2x10-9 M) [19]
Description: In a biochemical enzyme activity assay.
foretinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.6 pIC50 17
pIC50 8.6 (IC50 2.8x10-9 M) [17]
cediranib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition >8.5 pIC50 24
pIC50 >8.5 (IC50 <3x10-9 M) [24]
compound 8i [PMID: 22765894] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.5 pIC50 28
pIC50 8.5 (IC50 3x10-9 M) [28]
compound 8h [PMID: 22765894] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.5 pIC50 13
pIC50 8.5 (IC50 3.2x10-9 M) [13]
dovitinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 – 8.5 pIC50 20,22
pIC50 8.1 – 8.5 (IC50 8x10-9 – 3x10-9 M) [20,22]
lenvatinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 17
pIC50 8.3 (IC50 5.2x10-9 M) [17]
motesanib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.2 pIC50 17
pIC50 8.2 (IC50 6x10-9 M) [17]
tesevatinib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.1 pIC50 8
pIC50 8.1 (IC50 8.7x10-9 M) [8]
sunitinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 12
pIC50 8.1 (IC50 8.9x10-9 M) [12]
CS2164 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 29
pIC50 8.1 (IC50 9x10-9 M) [29]
Description: Inhibition in a biochemical assay.
tafetinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.9 pIC50 23
pIC50 7.9 (IC50 1.19x10-8 M) [23]
Description: In a radiometric biochemical protein kinase assay.
nintedanib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.9 pIC50 11
pIC50 7.9 (IC50 1.3x10-8 M) [11]
sorafenib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Mm Inhibition 7.7 pIC50 25
pIC50 7.7 (IC50 2x10-8 M) [25]
RIPK1 inhibitor 22b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.7 pIC50 14
pIC50 7.7 (IC50 2x10-8 M) [14]
pexmetinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 3
pIC50 7.4 (IC50 4.2x10-8 M) [3]
ilorasertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 9
pIC50 7.4 (IC50 4.3x10-8 M) [9]
Description: Measuring inhibition of kinase activity in a biochemical assay.
pazopanib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.3 pIC50 10
pIC50 7.3 (IC50 4.7x10-8 M) [10]
MK-2461 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 pIC50 18
pIC50 7.1 (IC50 7.8x10-8 M) [18]
CHMFL-KIT-64 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.9 pIC50 27
pIC50 6.9 (IC50 1.21x10-7 M) [27]
Description: In a biochemical assay.
VEGF receptor tyrosine kinase inhibitor III Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.9 pIC50 6
pIC50 6.9 (IC50 1.25x10-7 M) [6]
linifanib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.7 pIC50 1
pIC50 6.7 (IC50 1.9x10-7 M) [1]
vatalanib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.7 pIC50 15
pIC50 6.7 (IC50 1.95x10-7 M) [15]
CC-223 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.2 pIC50 16
pIC50 6.2 (IC50 6.51x10-7 M) [16]
View species-specific inhibitor tables
Inhibitor Comments
Note that pazopanib is a multi-target kinase inhibitor. See for [10] futher affinity data.
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 5,26

Key to terms and symbols Click column headers to sort
Target used in screen: FLT4
Ligand Sp. Type Action Value Parameter
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.8 pKd
cediranib Small molecule or natural product Hs Inhibitor Inhibition 8.4 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.0 pKd
motesanib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.0 pKd
linifanib Small molecule or natural product Hs Inhibitor Inhibition 7.8 pKd
lestaurtinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 7.8 pKd
pazopanib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 7.6 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.6 pKd
quizartinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 7.3 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 2,7

Key to terms and symbols Click column headers to sort
Target used in screen: Flt4/FLT4
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Small molecule or natural product Hs Inhibitor Inhibition 2.5 0.0 1.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.7 0.0 -1.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 4.3 -0.5 0.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 5.0 0.0 2.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 5.1 2.0 0.0
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 5.8 98.0 70.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 10.9 1.0 3.0
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 11.3
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 12.1 0.0 1.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 12.1 0.0 0.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0010575 positive regulation of vascular endothelial growth factor production IMP
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Hemangioma, capillary infantile
Synonyms: Familial capillary hemangioma [Orphanet: ORPHA91415]
OMIM: 602089
Orphanet: ORPHA91415
Disease:  Lymphedema, hereditary IA
Synonyms: Hereditary lymphedema [Disease Ontology: DOID:0050580]
Milroy disease [Orphanet: ORPHA79452]
Disease Ontology: DOID:0050580
OMIM: 153100
Orphanet: ORPHA79452

References

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1. Albert DH, Tapang P, Magoc TJ, Pease LJ, Reuter DR, Wei RQ, Li J, Guo J, Bousquet PF, Ghoreishi-Haack NS et al.. (2006) Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol. Cancer Ther., 5 (4): 995-1006. [PMID:16648571]

2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

3. Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, Giricz O, Sukrithan V, Nwankwo G, Shahnaz S et al.. (2016) Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res., 76 (16): 4841-4849. [PMID:27287719]

4. Chen GP. (2008) Spiro substituted compounds as angiogenesis inhibitors. Patent number: WO2008112407 A1. Assignee: Advenchen Laboratories, Llc. Priority date: 14/03/2007. Publication date: 18/09/2008.

5. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

6. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl. Acad. Sci. U.S.A., 104 (51): 20523-8. [PMID:18077363]

7. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

8. Gendreau SB, Ventura R, Keast P, Laird AD, Yakes FM, Zhang W, Bentzien F, Cancilla B, Lutman J, Chu F et al.. (2007) Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647. Clin. Cancer Res., 13 (12): 3713-23. [PMID:17575237]

9. Glaser KB, Li J, Marcotte PA, Magoc TJ, Guo J, Reuter DR, Tapang P, Wei RQ, Pease LJ, Bui MH et al.. (2012) Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families. J. Pharmacol. Exp. Ther., 343 (3): 617-27. [PMID:22935731]

10. Harris PA, Boloor A, Cheung M, Kumar R, Crosby RM, Davis-Ward RG, Epperly AH, Hinkle KW, Hunter 3rd RN, Johnson JH et al.. (2008) Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J. Med. Chem., 51 (15): 4632-40. [PMID:18620382]

11. Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J et al.. (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res., 68 (12): 4774-82. [PMID:18559524]

12. Khanwelkar RR, Chen GS, Wang HC, Yu CW, Huang CH, Lee O, Chen CH, Hwang CS, Ko CH, Chou NT et al.. (2010) Synthesis and structure-activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors. Bioorg. Med. Chem., 18 (13): 4674-86. [PMID:20570526]

13. Kim MH, Tsuhako AL, Co EW, Aftab DT, Bentzien F, Chen J, Cheng W, Engst S, Goon L, Klein RR et al.. (2012) The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett., 22 (15): 4979-85. [PMID:22765894]

14. Li Y, Xiong Y, Zhang G, Zhang L, Yang W, Yang J, Huang L, Qiao Z, Miao Z, Lin G et al.. (2018) Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. J. Med. Chem., 61 (24): 11398-11414. [PMID:30480444]

15. Manley PW, Furet P, Bold G, Brüggen J, Mestan J, Meyer T, Schnell CR, Wood J, Haberey M, Huth A et al.. (2002) Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors. J. Med. Chem., 45 (26): 5687-93. [PMID:12477352]

16. Mortensen DS, Perrin-Ninkovic SM, Shevlin G, Zhao J, Packard G, Bahmanyar S, Correa M, Elsner J, Harris R, Lee BG et al.. (2015) Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223. J. Med. Chem., 58 (13): 5323-33. [PMID:26083478]

17. Musumeci F, Radi M, Brullo C, Schenone S. (2012) Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors. J. Med. Chem., 55 (24): 10797-822. [PMID:23098265]

18. Pan BS, Chan GK, Chenard M, Chi A, Davis LJ, Deshmukh SV, Gibbs JB, Gil S, Hang G, Hatch H et al.. (2010) MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res., 70 (4): 1524-33. [PMID:20145145]

19. Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK. (2016) Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget, 7 (4): 4093-109. [PMID:26675259]

20. Renhowe PA, Pecchi S, Shafer CM, Machajewski TD, Jazan EM, Taylor C, Antonios-McCrea W, McBride CM, Frazier K, Wiesmann M et al.. (2009) Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors. J. Med. Chem., 52 (2): 278-92. [PMID:19113866]

21. Sun Q, Zhou J, Zhang Z, Guo M, Liang J, Zhou F, Long J, Zhang W, Yin F, Cai H et al.. (2014) Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol. Ther., 15 (12): 1635-45. [PMID:25482937]

22. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK. (2005) CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood, 105 (7): 2941-8. [PMID:15598814]

23. Wang D, Tang F, Wang S, Jiang Z, Zhang L. (2012) Preclinical anti-angiogenesis and anti-tumor activity of SIM010603, an oral, multi-targets receptor tyrosine kinases inhibitor. Cancer Chemother. Pharmacol., 69 (1): 173-83. [PMID:21638122]

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25. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M et al.. (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res., 64 (19): 7099-109. [PMID:15466206]

26. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

27. Wu Y, Wang B, Wang J, Qi S, Zou F, Qi Z, Liu F, Liu Q, Chen C, Hu C et al.. (2019) Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors. J. Med. Chem., 62 (13): 6083-6101. [PMID:31250638]

28. You WK, Sennino B, Williamson CW, Falcón B, Hashizume H, Yao LC, Aftab DT, McDonald DM. (2011) VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res., 71 (14): 4758-68. [PMID:21613405]

29. Zhou Y, Shan S, Li ZB, Xin LJ, Pan DS, Yang QJ, Liu YP, Yue XP, Liu XR, Gao JZ et al.. (2017) CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency. Cancer Sci., 108 (3): 469-477. [PMID:28004478]

How to cite this page

Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family: fms related receptor tyrosine kinase 4. Last modified on 06/03/2020. Accessed on 28/11/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1814.