fms related tyrosine kinase 1 | Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family | IUPHAR/BPS Guide to PHARMACOLOGY

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fms related tyrosine kinase 1

Target not currently curated in GtoImmuPdb

Target id: 1812

Nomenclature: fms related tyrosine kinase 1

Abbreviated Name: VEGFR-1

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 1 687 13q12 FLT1 fms related tyrosine kinase 1
Mouse 1 1333 5 G Flt1 FMS-like tyrosine kinase 1
Rat 1 1336 12p11 Flt1 FMS-related tyrosine kinase 1
Previous and Unofficial Names
fms-related tyrosine kinase 1 | vascular endothelial growth factor receptor 1
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of VEGFR1 (FLT1) in complex with N-(4-Chlorophenyl)-2-((pyridin-4-ylmethyl)amino)benzamide.
PDB Id:  3HNG
Resolution:  2.7Å
Species:  Human
References: 
Enzyme Reaction
EC Number: 2.7.10.1
Natural/Endogenous Ligands
VEGFA {Sp: Human}
VEGFB {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 Affinity Parameter Reference
compound 25 [PMID: 17935989] Hs Inhibition 6.4 pKi 27
pKi 6.4 (Ki 4.4x10-7 M) [27]
tivozanib Hs Inhibition 9.7 pIC50 21
pIC50 9.7 (IC50 2.1x10-10 M) [21]
foretinib Hs Inhibition 9.1 pIC50 21
pIC50 9.1 (IC50 8x10-10 M) [21]
VEGF receptor tyrosine kinase inhibitor III Hs Inhibition 9.0 pIC50 9
pIC50 9.0 (IC50 1x10-9 M) [9]
ilorasertib Hs Inhibition 9.0 pIC50 12
pIC50 9.0 (IC50 1x10-9 M) [12]
Description: Measuring inhibition of kinase activity in a biochemical assay.
motesanib Hs Inhibition 8.7 pIC50 21
pIC50 8.7 (IC50 2x10-9 M) [21]
SU-14813 Hs Inhibition 8.7 pIC50 24
pIC50 8.7 (IC50 2x10-9 M) [24]
linifanib Hs Inhibition 8.5 pIC50 1
pIC50 8.5 (IC50 3x10-9 M) [1]
CEP-11981 Hs Inhibition 8.5 pIC50 16
pIC50 8.5 (IC50 3x10-9 M) [16]
anlotinib Hs Inhibition 8.4 pIC50 7
pIC50 8.4 (IC50 4x10-9 M) [7]
Description: In vitro activity
cediranib Hs Inhibition 8.3 pIC50 30
pIC50 8.3 (IC50 5x10-9 M) [30]
dovitinib Hs Inhibition 8.0 – 8.5 pIC50 25,29
pIC50 8.0 – 8.5 (IC50 1x10-8 – 3x10-9 M) [25,29]
sitravatinib Hs Inhibition 8.2 pIC50 23
pIC50 8.2 (IC50 6x10-9 M) [23]
Description: In a biochemical enzyme activity assay.
compound 8h [PMID: 22765894] Hs Inhibition 8.1 pIC50 17
pIC50 8.1 (IC50 7.2x10-9 M) [17]
semaxanib Hs Inhibition 8.1 pIC50 6
pIC50 8.1 (IC50 8x10-9 M) [6]
OSI-930 Hs Inhibition 8.1 pIC50 11
pIC50 8.1 (IC50 8x10-9 M) [11]
pazopanib Hs Inhibition 8.0 pIC50 13
pIC50 8.0 (IC50 1x10-8 M) [13]
MK-2461 Hs Inhibition 8.0 pIC50 22
pIC50 8.0 (IC50 1x10-8 M) [22]
dorsomorphin Hs Inhibition 8.0 pIC50 20
pIC50 8.0 (IC50 1.1x10-8 M) [20]
Description: Assayed using AMPK heterotrimeric complex containing α2, β1, γ1 subunits
lucitanib Hs Inhibition 7.9 pIC50 32
pIC50 7.9 (IC50 1.2x10-8 M) [32]
compound 8i [PMID: 22765894] Hs Inhibition 7.7 pIC50 17
pIC50 7.7 (IC50 2x10-8 M) [17]
nintedanib Hs Inhibition 7.5 pIC50 15
pIC50 7.5 (IC50 3.1x10-8 M) [15]
Cdk1/2 inhibitor III Hs Inhibition 7.5 pIC50 19
pIC50 7.5 (IC50 3.2x10-8 M) [19]
fruquintinib Hs Inhibition 7.5 pIC50 26
pIC50 7.5 (IC50 3.3x10-8 M) [26]
Description: Evaluated in a [32]p-ATP incorporation assay
pexmetinib Hs Inhibition 7.3 pIC50 4
pIC50 7.3 (IC50 4.7x10-8 M) [4]
vatalanib Hs Inhibition 6.8 pIC50 18
pIC50 6.8 (IC50 1.4x10-7 M) [18]
brivanib Hs Inhibition 6.4 pIC50 5
pIC50 6.4 (IC50 3.8x10-7 M) [5]
ZM-306416 Hs Inhibition 5.7 – 6.5 pIC50 3,14
pIC50 5.7 – 6.5 (IC50 2x10-6 – 3.3x10-7 M) [3,14]
pexidartinib Hs Inhibition 6.1 pIC50 28
pIC50 6.1 (IC50 8.8x10-7 M) [28]
Inhibitor Comments
Note that pazopanib is a multi-target kinase inhibitor. See for [13] futher affinity data.
Compound 25 [PMID 17935989] is a CHK1 inhibitor and interacts with VEGFR1 as an off-target. Inhibiton of CHK1 is >100 times more potent than inhibition of VEGFR1 [...].
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: 8,31

Key to terms and symbols Click column headers to sort
Target used in screen: FLT1
Ligand Sp. Type Action Affinity Parameter
cediranib Hs Inhibitor Inhibition 9.1 pKd
sunitinib Hs Inhibitor Inhibition 8.7 pKd
foretinib Hs Inhibitor Inhibition 8.4 pKd
SU-14813 Hs Inhibitor Inhibition 8.3 pKd
axitinib Hs Inhibitor Inhibition 8.2 pKd
linifanib Hs Inhibitor Inhibition 8.1 pKd
vatalanib Hs Inhibitor Inhibition 8.0 pKd
brivanib Hs Inhibitor Inhibition 8.0 pKd
motesanib Hs Inhibitor Inhibition 7.9 pKd
pazopanib Hs Inhibitor Inhibition 7.8 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: 2,10

Key to terms and symbols Click column headers to sort
Target used in screen: Flt1/FLT1(VEGFR1)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 3.1 115.0 89.0
staurosporine Hs Inhibitor Inhibition 7.9 0.0 -0.5
TWS119 Hs Inhibitor Inhibition 8.6 0.0 0.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 11.4 0.0 -1.0
SB 218078 Hs Inhibitor Inhibition 13.3 7.0 4.0
Gö 6983 Hs Inhibitor Inhibition 22.0 2.0 0.0
K-252a Hs Inhibitor Inhibition 23.2 0.0 0.0
VEGF receptor tyrosine kinase inhibitor II Hs Inhibitor Inhibition 24.8 0.0 2.0
dovitinib Hs Inhibitor Inhibition 26.2
pazopanib Hs Inhibitor Inhibition 27.2
Displaying the top 10 most potent ligands  View all ligands in screen »

References

Show »

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. Antczak C, Mahida JP, Bhinder B, Calder PA, Djaballah H. (2012) A high-content biosensor-based screen identifies cell-permeable activators and inhibitors of EGFR function: implications in drug discovery. J Biomol Screen, 17 (7): 885-99. [PMID:22573732]

4. 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]

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6. Bold G, Altmann KH, Frei J, Lang M, Manley PW, Traxler P, Wietfeld B, Brüggen J, Buchdunger E, Cozens R et al.. (2000) New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J. Med. Chem., 43 (12): 2310-23. [PMID:10882357]

7. 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.

8. 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]

9. 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]

10. 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]

11. Garton AJ, Crew AP, Franklin M, Cooke AR, Wynne GM, Castaldo L, Kahler J, Winski SL, Franks A, Brown EN et al.. (2006) OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res., 66 (2): 1015-24. [PMID:16424037]

12. 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]

13. 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]

14. Hennequin LF, Thomas AP, Johnstone C, Stokes ES, Plé PA, Lohmann JJ, Ogilvie DJ, Dukes M, Wedge SR, Curwen JO et al.. (1999) Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors. J. Med. Chem., 42 (26): 5369-89. [PMID:10639280]

15. 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]

16. Hudkins RL, Becknell NC, Zulli AL, Underiner TL, Angeles TS, Aimone LD, Albom MS, Chang H, Miknyoczki SJ, Hunter K et al.. (2012) Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent. J. Med. Chem., 55 (2): 903-13. [PMID:22148921]

17. 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]

18. Kiselyov AS, Semenova M, Semenov VV, Piatnitski E, Ouyang S. (2006) Hetaryl imidazoles: a novel dual inhibitors of VEGF receptors I and II. Bioorg. Med. Chem. Lett., 16 (5): 1440-4. [PMID:16321531]

19. Lin R, Connolly PJ, Huang S, Wetter SK, Lu Y, Murray WV, Emanuel SL, Gruninger RH, Fuentes-Pesquera AR, Rugg CA et al.. (2005) 1-Acyl-1H-[1,2,4]triazole-3,5-diamine analogues as novel and potent anticancer cyclin-dependent kinase inhibitors: synthesis and evaluation of biological activities. J. Med. Chem., 48 (13): 4208-11. [PMID:15974571]

20. Machrouhi F, Ouhamou N, Laderoute K, Calaoagan J, Bukhtiyarova M, Ehrlich PJ, Klon AE. (2010) The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity. Bioorg. Med. Chem. Lett., 20 (22): 6394-9. [PMID:20932747]

21. 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]

22. 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]

23. 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]

24. Patyna S, Laird AD, Mendel DB, O'farrell AM, Liang C, Guan H, Vojkovsky T, Vasile S, Wang X, Chen J et al.. (2006) SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity. Mol. Cancer Ther., 5 (7): 1774-82. [PMID:16891463]

25. 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]

26. 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]

27. Tao ZF, Chen Z, Bui MH, Kovar P, Johnson E, Bouska J, Zhang H, Rosenberg S, Sowin T, Lin NH. (2007) Macrocyclic ureas as potent and selective Chk1 inhibitors: an improved synthesis, kinome profiling, structure-activity relationships, and preliminary pharmacokinetics. Bioorg. Med. Chem. Lett., 17 (23): 6593-601. [PMID:17935989]

28. Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, Chmielowski B, Staddon AP, Cohn AL, Shapiro GI et al.. (2015) Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. N. Engl. J. Med., 373 (5): 428-37. [PMID:26222558]

29. 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]

30. 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]

31. 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]

32. Zhou Y, Chen Y, Tong L, Xie H, Wen W, Zhang J, Xi Y, Shen Y, Geng M, Wang Y et al.. (2012) AL3810, a multi-tyrosine kinase inhibitor, exhibits potent anti-angiogenic and anti-tumour activity via targeting VEGFR, FGFR and PDGFR. J. Cell. Mol. Med., 16 (10): 2321-30. [PMID:22304225]

How to cite this page

Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family: fms related tyrosine kinase 1. Last modified on 24/04/2018. Accessed on 23/04/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1812.