fibroblast growth factor receptor 4 | Type V RTKs: FGF (fibroblast growth factor) receptor family | IUPHAR/BPS Guide to PHARMACOLOGY

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fibroblast growth factor receptor 4

Target not currently curated in GtoImmuPdb

Target id: 1811

Nomenclature: fibroblast growth factor receptor 4

Abbreviated Name: FGFR4

Family: Type V RTKs: FGF (fibroblast 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 1 802 5q33-qter FGFR4 fibroblast growth factor receptor 4
Mouse 1 799 13 Fgfr4 fibroblast growth factor receptor 4
Rat 1 800 17p14 Fgfr4 fibroblast growth factor receptor 4
Previous and Unofficial Names
Protein-tyrosine kinase receptor MPK-11 | CD334 | JTK2
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of FGFR4 with an irreversible inhibitor (BLU9931).
PDB Id:  4XCU
Ligand:  BLU-9931
Resolution:  1.71Å
Species:  Human
References:  9
Enzyme Reaction
EC Number: 2.7.10.1
Endogenous ligands (Human)
FGF-1 (FGF1, P05230), FGF-2 (FGF2, P09038), FGF-4 (FGF4, P08620), FGF-9 (FGF9, P31371) > FGF-6 (FGF6, P10767), FGF-8 (FGF8, P55075)  [13]

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
roblitinib Hs Inhibition 8.7 pIC50 5
pIC50 8.7 (IC50 1.9x10-9 M) [5]
Description: In a biochemical enzyme assay.
BLU-9931 Hs Irreversible inhibition 8.5 pIC50 9
pIC50 8.5 (IC50 3x10-9 M) [9]
futibatinib Hs Inhibition 8.5 pIC50 14
pIC50 8.5 (IC50 3.4x10-9 M) [14]
erdafitinib Hs Inhibition 8.3 pIC50 15
pIC50 8.3 (IC50 5.62x10-9 M) [15]
LY2874455 Hs Inhibition 8.2 pIC50 19
pIC50 8.2 (IC50 6x10-9 M) [19]
BLU-554 Hs Irreversible inhibition >8.0 pIC50 3
pIC50 >8.0 (IC50 <1x10-8 M) [3]
Description: Determined using Caliper LifeSciences electrophoretic mobility shift technology.
PRN1371 Hs Inhibition 7.7 pIC50 4
pIC50 7.7 (IC50 1.93x10-8 M) [4]
infigratinib Hs Inhibition 7.2 pIC50 8
pIC50 7.2 (IC50 6x10-8 M) [8]
AZD4547 Hs Inhibition 6.8 pIC50 2
pIC50 6.8 (IC50 1.65x10-7 M) [2]
DEBIO1347 Hs Inhibition 6.5 pIC50 12
pIC50 6.5 (IC50 2.9x10-7 M) [12]
nintedanib Hs Inhibition 6.2 pIC50 10
pIC50 6.2 (IC50 6.1x10-7 M) [10]
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: 6,17

Key to terms and symbols Click column headers to sort
Target used in screen: FGFR4
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Hs Inhibitor Inhibition 7.0 pKd
staurosporine Hs Inhibitor Inhibition 6.6 pKd
tamatinib Hs Inhibitor Inhibition 6.5 pKd
PD-173955 Hs Inhibitor Inhibition 6.3 pKd
brivanib Hs Inhibitor Inhibition 6.2 pKd
cediranib Hs Inhibitor Inhibition 6.1 pKd
PP-242 Hs Inhibitor Inhibition 6.0 pKd
AST-487 Hs Inhibitor Inhibition 5.8 pKd
lestaurtinib Hs Inhibitor Inhibition 5.7 pKd
fedratinib Hs Inhibitor Inhibition 5.7 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: 1,7

Key to terms and symbols Click column headers to sort
Target used in screen: FGFR4/FGFR4
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 32.2 71.0 23.0
TWS119 Hs Inhibitor Inhibition 45.1 72.0 22.0
staurosporine Hs Inhibitor Inhibition 47.2 49.0 15.0
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 58.0 118.0 106.0
dovitinib Hs Inhibitor Inhibition 59.6
indirubin derivative E804 Hs Inhibitor Inhibition 65.7 91.0 36.0
pazopanib Hs Inhibitor Inhibition 68.3
semaxanib Hs Inhibitor Inhibition 69.3 124.0 93.0
SB 218078 Hs Inhibitor Inhibition 70.4 103.0 102.0
SU11652 Hs Inhibitor Inhibition 70.5 101.0 47.0
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:0090272 negative regulation of fibroblast growth factor production IGI
General Comments
FGFR4 is a targetable regulator of chemo-resistance in colorectal cancer [11,16,18]. Selective FGFR4 inhibitors are predicted to enhance the effectiveness of chemotherapeutics in this disease. Incyte's orally bioavailable FGFR4 inhibitor INCB‐062079 blocks FGFR4 autophosphorylation and activation of receptor tyrosine kinase activity that would normally occur after binding to its ligand fibroblast growth factor 19 (FGF19). INCB‐062079 inhibits FGFR4-mediated signaling and this action precipitates an inhibition of tumour cell proliferation in FGF19- and FGFR4-overexpressing cells.

References

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1. 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]

2. AstraZeneca. AZD4547. Accessed on 11/09/2014. Modified on 11/09/2014. astrazeneca.com, http://openinnovation.astrazeneca.com/what-we-offer/compound/azd4547/

3. Bifulco N, Dipietro LV, Hodous BL, Miduturu CV. (2015) Inhibitors of the fibroblast growth factor receptor. Patent number: WO2015061572A1. Assignee: Blueprint Medicines. Priority date: 25/10/2013. Publication date: 30/04/2015.

4. Brameld KA, Owens TD, Verner E, Venetsanakos E, Bradshaw JM, Phan VT, Tam D, Leung K, Shu J, LaStant J et al.. (2017) Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors. J. Med. Chem., 60 (15): 6516-6527. [PMID:28665128]

5. Buschmann N, Fairhurst RA, Furet P, Knöpfel T, Leblanc C, Liao LV, Mah R, Nimsgen P, Ripoche S, Xiong J et al.. (2016) Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors. Patent number: US9266883. Assignee: Novartis Ag. Priority date: 25/10/2013. Publication date: 23/02/2016.

6. 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]

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. Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, Brueggen J, Jensen MR, Schnell C, Schmid H et al.. (2011) Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J. Med. Chem., 54 (20): 7066-83. [PMID:21936542]

9. Hagel M, Miduturu C, Sheets M, Rubin N, Weng W, Stransky N, Bifulco N, Kim JL, Hodous B, Brooijmans N et al.. (2015) First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer Discov, 5 (4): 424-37. [PMID:25776529]

10. 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]

11. Lang L, Shull AY, Teng Y. (2019) Interrupting the FGF19-FGFR4 Axis to Therapeutically Disrupt Cancer Progression. Curr Cancer Drug Targets, 19 (1): 17-25. [PMID:29557750]

12. Nakanishi Y, Akiyama N, Tsukaguchi T, Fujii T, Sakata K, Sase H, Isobe T, Morikami K, Shindoh H, Mio T et al.. (2014) The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. Mol. Cancer Ther., 13 (11): 2547-58. [PMID:25169980]

13. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M. (1996) Receptor specificity of the fibroblast growth factor family. J. Biol. Chem., 271 (25): 15292-7. [PMID:8663044]

14. Sagara T, Ito S, Otsuki S, Sootome H. (2013) 3,5-disubstituted alkynylbenzene compound and salt thereof. Patent number: WO2013108809. Assignee: Taiho Pharmaceutical Co., Ltd.. Priority date: 19/01/2012. Publication date: 25/07/2013.

15. Saxty G, Murray CW, Berdini V, Besong GE, Hamlett CCF, Johnson CN, Woodhead SJ, Reader M, Rees DC, Mevellec LA et al.. (2011) Pyrazolyl quinazoline kinase inhibitors. Patent number: WO2011135376 A1. Assignee: Astex Therapeutics Limited. Priority date: 30/04/2010. Publication date: 03/11/2011.

16. Turkington RC, Longley DB, Allen WL, Stevenson L, McLaughlin K, Dunne PD, Blayney JK, Salto-Tellez M, Van Schaeybroeck S, Johnston PG. (2014) Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer. Cell Death Dis, 5: e1046. [PMID:24503538]

17. 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]

18. Yamamoto M, Nomura S, Hosoi A, Nagaoka K, Iino T, Yasuda T, Saito T, Matsushita H, Uchida E, Seto Y et al.. (2018) Established gastric cancer cell lines transplantable into C57BL/6 mice show fibroblast growth factor receptor 4 promotion of tumor growth. Cancer Sci., 109 (5): 1480-1492. [PMID:29532565]

19. Zhao G, Li WY, Chen D, Henry JR, Li HY, Chen Z, Zia-Ebrahimi M, Bloem L, Zhai Y, Huss K et al.. (2011) A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol. Cancer Ther., 10 (11): 2200-10. [PMID:21900693]

How to cite this page

Type V RTKs: FGF (fibroblast growth factor) receptor family: fibroblast growth factor receptor 4. Last modified on 07/08/2019. Accessed on 31/05/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1811.