fms related tyrosine kinase 4 | Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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fms related tyrosine kinase 4

Target not currently curated in GtoImmuPdb

Target id: 1814

Nomenclature: fms related tyrosine kinase 4

Abbreviated Name: VEGFR-3

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

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1298 5q34-q35 FLT4 fms related tyrosine kinase 4
Mouse 1 1363 11 A5-B1 Flt4 FMS-like tyrosine kinase 4
Rat 1 1363 10q22 Flt4 fms-related tyrosine kinase 4
Previous and Unofficial Names
PCL | vascular endothelial growth factor receptor 3
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 2.7.10.1
Natural/Endogenous Ligands
VEGFC {Sp: Human}
VEGFD {Sp: Human}
VEGFE {Sp: Human}

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
tivozanib Hs Inhibition 9.6 pIC50 17
pIC50 9.6 (IC50 2.4x10-10 M) [17]
fruquintinib Hs Inhibition 9.3 pIC50 21
pIC50 9.3 (IC50 5x10-10 M) [21]
Description: Evaluated in a [32]p-ATP incorporation assay
anlotinib Hs Inhibition 9.0 pIC50 4
pIC50 9.0 (IC50 1x10-9 M) [4]
Description: In vitro activity
sitravatinib Hs Inhibition 8.7 pIC50 19
pIC50 8.7 (IC50 2x10-9 M) [19]
Description: In a biochemical enzyme activity assay.
foretinib Hs Inhibition 8.6 pIC50 17
pIC50 8.6 (IC50 2.8x10-9 M) [17]
cediranib Hs Inhibition >8.5 pIC50 24
pIC50 >8.5 (IC50 <3x10-9 M) [24]
compound 8i [PMID: 22765894] Hs Inhibition 8.5 pIC50 28
pIC50 8.5 (IC50 3x10-9 M) [28]
compound 8h [PMID: 22765894] Hs Inhibition 8.5 pIC50 13
pIC50 8.5 (IC50 3.2x10-9 M) [13]
dovitinib Hs Inhibition 8.1 – 8.5 pIC50 20,22
pIC50 8.1 – 8.5 (IC50 8x10-9 – 3x10-9 M) [20,22]
lenvatinib Hs Inhibition 8.3 pIC50 17
pIC50 8.3 (IC50 5.2x10-9 M) [17]
motesanib Hs Inhibition 8.2 pIC50 17
pIC50 8.2 (IC50 6x10-9 M) [17]
tesevatinib Hs Inhibition 8.1 pIC50 8
pIC50 8.1 (IC50 8.7x10-9 M) [8]
sunitinib Hs Inhibition 8.1 pIC50 12
pIC50 8.1 (IC50 8.9x10-9 M) [12]
CS2164 Hs Inhibition 8.1 pIC50 29
pIC50 8.1 (IC50 9x10-9 M) [29]
Description: Inhibition in a biochemical assay.
tafetinib Hs Inhibition 7.9 pIC50 23
pIC50 7.9 (IC50 1.19x10-8 M) [23]
Description: In a radiometric biochemical protein kinase assay.
nintedanib Hs Inhibition 7.9 pIC50 11
pIC50 7.9 (IC50 1.3x10-8 M) [11]
sorafenib Mm Inhibition 7.7 pIC50 25
pIC50 7.7 (IC50 2x10-8 M) [25]
RIPK1 inhibitor 22b Hs Inhibition 7.7 pIC50 14
pIC50 7.7 (IC50 2x10-8 M) [14]
pexmetinib Hs Inhibition 7.4 pIC50 3
pIC50 7.4 (IC50 4.2x10-8 M) [3]
ilorasertib 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 Hs Inhibition 7.3 pIC50 10
pIC50 7.3 (IC50 4.7x10-8 M) [10]
MK-2461 Hs Inhibition 7.1 pIC50 18
pIC50 7.1 (IC50 7.8x10-8 M) [18]
CHMFL-KIT-64 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 Hs Inhibition 6.9 pIC50 6
pIC50 6.9 (IC50 1.25x10-7 M) [6]
linifanib Hs Inhibition 6.7 pIC50 1
pIC50 6.7 (IC50 1.9x10-7 M) [1]
vatalanib Hs Inhibition 6.7 pIC50 15
pIC50 6.7 (IC50 1.95x10-7 M) [15]
CC-223 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
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 Hs Inhibitor Inhibition 8.8 pKd
cediranib Hs Inhibitor Inhibition 8.4 pKd
tamatinib Hs Inhibitor Inhibition 8.0 pKd
motesanib Hs Inhibitor Inhibition 8.0 pKd
linifanib Hs Inhibitor Inhibition 7.8 pKd
lestaurtinib Hs Inhibitor Inhibition 7.8 pKd
pazopanib Hs Inhibitor Inhibition 7.6 pKd
staurosporine Hs Inhibitor Inhibition 7.6 pKd
quizartinib Hs Inhibitor Inhibition 7.4 pKd
SU-14813 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
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 Hs Inhibitor Inhibition 2.5 0.0 1.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 3.7 0.0 -1.0
staurosporine Hs Inhibitor Inhibition 4.3 -0.5 0.0
SB 218078 Hs Inhibitor Inhibition 5.0 0.0 2.0
JAK3 inhibitor VI Hs Inhibitor Inhibition 5.1 2.0 0.0
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 5.8 98.0 70.0
midostaurin Hs Inhibitor Inhibition 10.9 1.0 3.0
dovitinib Hs Inhibitor Inhibition 11.3
SU11652 Hs Inhibitor Inhibition 12.1 0.0 1.0
PKR inhibitor Hs Inhibitor Inhibition 12.1 0.0 0.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
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]

24. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO et al.. (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res., 65 (10): 4389-400. [PMID:15899831]

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 tyrosine kinase 4. Last modified on 04/09/2019. Accessed on 11/12/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1814.