Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRQERG2)

• DOT Name: Fibroblast growth factor receptor 4 (FGFR4)
• Synonyms: FGFR-4; EC 2.7.10.1; CD antigen CD334
• Gene Name: FGFR4
• UniProt ID: FGFR4_HUMAN
• PDB ID: 4QQ5 ; 4QQC ; 4QQJ ; 4QQT ; 4QRC ; 4R6V ; 4TYE ; 4TYG ; 4TYI ; 4TYJ ; 4UXQ ; 4XCU ; 5JKG ; 5NUD ; 5NWZ ; 5XFF ; 5XFJ ; 6IUO ; 6IUP ; 6J6Y ; 6JPE ; 6JPJ ; 6NVG ; 6NVH ; 6NVI ; 6NVJ ; 6NVK ; 6V9C ; 6YI8 ; 7DTZ ; 7F3M ; 7N1J ; 7TYD ; 7V29 ; 7VJL ; 7WCT ; 7WCW ; 7WCX ; 7YBO ; 7YBP ; 7YBX ; 7YC1 ; 7YC3 ; 7YSW
• EC Number: 2.7.10.1
• Pfam ID: PF07679 ; PF13927 ; PF07714
• Sequence:
  MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRA
  ERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDS
  LTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTP
  TIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLD
  VLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFP
  YVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTA
  AAPEARYTDIILYASGSLALAVLLLLAGLYRGQALHGRHPRPPATVQKLSRFPLARQFSL
  ESGSSGKSSSSLVRGVRLSSSGPALLAGLVSLDLPLDPLWEFPRDRLVLGKPLGEGCFGQ
  VVRAEAFGMDPARPDQASTVAVKMLKDNASDKDLADLVSEMEVMKLIGRHKNIINLLGVC
  TQEGPLYVIVECAAKGNLREFLRARRPPGPDLSPDGPRSSEGPLSFPVLVSCAYQVARGM
  QYLESRKCIHRDLAARNVLVTEDNVMKIADFGLARGVHHIDYYKKTSNGRLPVKWMAPEA
  LFDRVYTHQSDVWSFGILLWEIFTLGGSPYPGIPVEELFSLLREGHRMDRPPHCPPELYG
  LMRECWHAAPSQRPTFKQLVEALDKVLLAVSEEYLDLRLTFGPYSPSGGDASSTCSSSDS
  VFSHDPLPLGSSSFPFGSGVQT
• Function: Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.
• Tissue Specificity: Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  Endocytosis (hsa04144)
  PI3K-Akt sig.ling pathway (hsa04151)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Regulation of actin cytoskeleton (hsa04810)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  (FGFR4)
  PIP3 activates AKT signaling (R-HSA-1257604)
  betaKlotho-mediated ligand binding (R-HSA-1307965)
  FGFR4 mutant receptor activation (R-HSA-1839128)
  FGFR4 ligand binding and activation (R-HSA-190322)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Phospholipase C-mediated cascade (R-HSA-5654228)
  FRS-mediated FGFR4 signaling (R-HSA-5654712)
  SHC-mediated cascade (R-HSA-5654719)
  PI-3K cascade (R-HSA-5654720)
  Negative regulation of FGFR4 signaling (R-HSA-5654733)
  Signaling by FGFR4 in disease (R-HSA-5655291)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
ANW-32821	DMMJOZD	Phase 2	Fibroblast growth factor receptor 4 (FGFR4) decreases the metabolism of ANW-32821.	[17]

15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Fibroblast growth factor receptor 4 (FGFR4).	[2]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Fibroblast growth factor receptor 4 (FGFR4).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Fibroblast growth factor receptor 4 (FGFR4).	[15]
PD173074	DMP0N4U	Investigative	PD173074 decreases the activity of Fibroblast growth factor receptor 4 (FGFR4).	[16]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ardeparin	DMYRX8B	Approved	Ardeparin affects the binding of Fibroblast growth factor receptor 4 (FGFR4).	[12]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Fibroblast growth factor receptor 4 (FGFR4).	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Fibroblast growth factor receptor 4 (FGFR4).	[13]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Modulation of fibroblast growth factor receptor expression and signalling during retinoic acid-induced differentiation of Tera-2 teratocarcinoma cells. Biochem Biophys Res Commun. 1993 Feb 26;191(1):149-56. doi: 10.1006/bbrc.1993.1196.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] A new function of copper zinc superoxide dismutase: as a regulatory DNA-binding protein in gene expression in response to intracellular hydrogen peroxide. Nucleic Acids Res. 2019 Jun 4;47(10):5074-5085. doi: 10.1093/nar/gkz256.
• [8] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [12] Binding of heparin/heparan sulfate to fibroblast growth factor receptor 4. J Biol Chem. 2001 May 18;276(20):16868-76. doi: 10.1074/jbc.M011226200. Epub 2001 Feb 21.
• [13] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [14] Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8.
• [15] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [16] Cooperation between fibroblast growth factor receptor-4 and ErbB2 in regulation of cyclin D1 translation. J Biol Chem. 2004 Nov 26;279(48):50004-11. doi: 10.1074/jbc.M404252200. Epub 2004 Sep 17.
• [17] Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids. J Biol Chem. 2005 May 6;280(18):17707-14. doi: 10.1074/jbc.M411771200. Epub 2005 Mar 4.