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fibroblast growth factor receptor 4

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Target id: 1811

Nomenclature: fibroblast growth factor receptor 4

Abbreviated Name: FGFR4

Family: Type V RTKs: FGF (fibroblast growth factor) receptor family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 802 5q35.2 FGFR4 fibroblast growth factor receptor 4
Mouse 1 799 13 29.8 cM Fgfr4 fibroblast growth factor receptor 4
Rat 1 800 17p14 Fgfr4 fibroblast growth factor receptor 4
Previous and Unofficial Names Click here for help
Protein-tyrosine kinase receptor MPK-11 | CD334 | JTK2
Database Links Click here for help
Alphafold P22455 (Hs), Q03142 (Mm), Q498D6 (Rn)
BRENDA 2.7.10.1
CATH/Gene3D 2.60.40.10
ChEMBL Target CHEMBL3973 (Hs), CHEMBL3839 (Mm), CHEMBL4802008 (Rn)
Ensembl Gene ENSG00000160867 (Hs), ENSMUSG00000005320 (Mm), ENSRNOG00000016763 (Rn)
Entrez Gene 2264 (Hs), 14186 (Mm), 25114 (Rn)
Human Protein Atlas ENSG00000160867 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:2264 (Hs), mmu:14186 (Mm), rno:25114 (Rn)
OMIM 134935 (Hs)
Pharos P22455 (Hs)
RefSeq Nucleotide NM_002011 (Hs), NM_008011 (Mm), NM_001109904 (Rn)
RefSeq Protein NP_002002 (Hs), NP_032037 (Mm), NP_001103374 (Rn)
SynPHARM 82936 (in complex with BLU9931)
UniProtKB P22455 (Hs), Q03142 (Mm), Q498D6 (Rn)
Wikipedia FGFR4 (Hs)
Selected 3D Structures Click here for help
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:  10
Enzyme Reaction Click here for help
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): FGF-19 (FGF19, O95750)  [15]

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
roblitinib Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.7 pIC50 5
⤷ pIC50 8.7 (IC50 1.9x10-9 M) [5]
Description: In a biochemical enzyme assay.
BLU-9931 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Irreversible inhibition 8.5 pIC50 10
⤷ pIC50 8.5 (IC50 3x10-9 M) [10]
futibatinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.5 pIC50 17
⤷ pIC50 8.5 (IC50 3.4x10-9 M) [17]
compound A34 [PMID: 35635004] Small molecule or natural product Primary target of this compound Hs Inhibition 8.3 pIC50 25
⤷ pIC50 8.3 (IC50 5.4x10-9 M) [25]
erdafitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 18
⤷ pIC50 8.3 (IC50 5.62x10-9 M) [18]
LY2874455 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.2 pIC50 26
⤷ pIC50 8.2 (IC50 6x10-9 M) [26]
irpagratinib Small molecule or natural product Hs Inhibition 8.1 pIC50 24
⤷ pIC50 8.1 (IC50 8.5x10-9 M) [24]
fisogatinib Small molecule or natural product Primary target of this compound Hs Irreversible inhibition >8.0 – 8.1 pIC50 3,25
⤷ pIC50 8.1 (IC50 8.8x10-9 M) [25]
pIC50 >8.0 (IC50 <1x10-8 M) [3]
Description: Determined using Caliper LifeSciences electrophoretic mobility shift technology.
PRN1371 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.7 pIC50 4
⤷ pIC50 7.7 (IC50 1.93x10-8 M) [4]
segigratinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.3 pIC50 16
⤷ pIC50 7.3 (IC50 5.14x10-8 M) [16]
infigratinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.2 pIC50 9
⤷ pIC50 7.2 (IC50 6x10-8 M) [9]
compound 29 [PMID: 36356320] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.8 pIC50 19
⤷ pIC50 6.8 (IC50 1.45x10-7 M) [19]
fexagratinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.8 pIC50 2
⤷ pIC50 6.8 (IC50 1.65x10-7 M) [2]
zoligratinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.5 pIC50 13
⤷ pIC50 6.5 (IC50 2.9x10-7 M) [13]
compound 7 [Nguyen et al., 2023] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.4 pIC50 14
⤷ pIC50 6.4 (IC50 3.51x10-7 M) [14]
nintedanib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.2 pIC50 11
⤷ pIC50 6.2 (IC50 6.1x10-7 M) [11]
tasurgratinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.2 pIC50 7
⤷ pIC50 6.2 (IC50 6.44x10-7 M) [7]
Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
FGF-19 {Sp: Human} Peptide Ligand is endogenous in the given species Hs Binding 9.0 pKd 22
⤷ pKd 9.0 (Kd 1x10-9 M) [22]
Description: Binding is heparin dependent
aldafermin Peptide Hs Binding - - 27
⤷ [27]
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: 6,21
Key to terms and symbols Click column headers to sort
Target used in screen: FGFR4
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.5 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
brivanib Small molecule or natural product Hs Inhibitor Inhibition 6.2 pKd
cediranib Small molecule or natural product Hs Inhibitor Inhibition 6.1 pKd
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.0 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 5.8 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.7 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure 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 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: 1,8
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 32.2 71.0 23.0
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 45.1 72.0 22.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 47.2 49.0 15.0
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 58.0 118.0 106.0
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 59.6
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 65.7 91.0 36.0
pazopanib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 68.3
semaxanib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 69.3 124.0 93.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 70.4 103.0 102.0
SU11652 Small molecule or natural product Ligand has a PDB structure 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
General Comments
FGFR4 is a targetable regulator of chemo-resistance in colorectal cancer [12,20,23]. 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. Funasaka S, Okada S, Tanaka K, Nagao S, Ohashi I, Yamane Y, Nakatani Y,Karouji Y. (2014) Monocyclic pyridine derivative. Patent number: WO2014129477A1. Assignee: Eisai R & D. Priority date: 20/02/2013. Publication date: 28/08/2014.

8. 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]

9. 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]

10. 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]

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. 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]

13. 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]

14. Nguyen MH, Ye HF, Xu Y, Truong L, Horsey A, Styduhar ED, Frascella M, Leffet L, Federowicz K, Behshad E et al.. (2023) Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scaffold Repurposing Approach. ACS Medicinal Chemistry Letters, 14 (3): 312–318. DOI: 10.1021/acsmedchemlett.3c00003

15. 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]

16. Peng X, Hou P, Chen Y, Dai Y, Ji Y, Shen Y, Su Y, Liu B, Wang Y, Sun D et al.. (2019) Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models. J Exp Clin Cancer Res, 38 (1): 372. [PMID:31438996]

17. 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.

18. 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.

19. Shvartsbart A, Roach JJ, Witten MR, Koblish H, Harris JJ, Covington M, Hess R, Lin L, Frascella M, Truong L et al.. (2022) Discovery of Potent and Selective Inhibitors of Wild-Type and Gatekeeper Mutant Fibroblast Growth Factor Receptor (FGFR) 2/3. J Med Chem, 65 (22): 15433-15442. [PMID:36356320]

20. 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]

21. 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]

22. Xie MH, Holcomb I, Deuel B, Dowd P, Huang A, Vagts A, Foster J, Liang J, Brush J, Gu Q et al.. (1999) FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine, 11 (10): 729-35. [PMID:10525310]

23. 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]

24. Yang F, Deng H, Ying H, Yu H, Chen Z, Xu Y. (2021) FGFR4 inhibitor, preparation method therefor and pharmaceutical use thereof. Patent number: US10968220B2. Assignee: Abbisko Therapeutics Co Ltd. Priority date: 14/12/2017. Publication date: 06/04/2021.

25. Zhang X, Wang Y, Ji J, Si D, Bao X, Yu Z, Zhu Y, Zhao L, Li W, Liu J. (2022) Discovery of 1,6-Naphthyridin-2(1H)-one Derivatives as Novel, Potent, and Selective FGFR4 Inhibitors for the Treatment of Hepatocellular Carcinoma. J Med Chem, 65 (11): 7595-7618. [PMID:35635004]

26. 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]

27. Zhou M, Wang X, Phung V, Lindhout DA, Mondal K, Hsu JY, Yang H, Humphrey M, Ding X, Arora T et al.. (2014) Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19. Cancer Res, 74 (12): 3306-16. [PMID:24728076]

How to cite this page

Type V RTKs: FGF (fibroblast growth factor) receptor family: fibroblast growth factor receptor 4. Last modified on 06/03/2024. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1811.