Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8I64X8)

• DOT Name: Fibroblast growth factor 1 (FGF1)
• Synonyms: FGF-1; Acidic fibroblast growth factor; aFGF; Endothelial cell growth factor; ECGF; Heparin-binding growth factor 1; HBGF-1
• Gene Name: FGF1
• UniProt ID: FGF1_HUMAN
• PDB ID: 1AXM ; 1DJS ; 1DZC ; 1DZD ; 1E0O ; 1EVT ; 1HKN ; 1JQZ ; 1JT3 ; 1JT4 ; 1JT5 ; 1JT7 ; 1JTC ; 1JY0 ; 1K5U ; 1K5V ; 1M16 ; 1NZK ; 1P63 ; 1PZZ ; 1Q03 ; 1Q04 ; 1RG8 ; 1RML ; 1RY7 ; 1YTO ; 1Z2V ; 1Z4S ; 2AFG ; 2AQZ ; 2AXM ; 2ERM ; 2HW9 ; 2HWA ; 2HWM ; 2HZ9 ; 2K43 ; 2K4A ; 2K8R ; 2KI4 ; 2KI6 ; 2NTD ; 2Q9X ; 2RQ9 ; 3B9U ; 3BA4 ; 3BA5 ; 3BA7 ; 3BAD ; 3BAG ; 3BAH ; 3BAO ; 3BAQ ; 3BAU ; 3BAV ; 3BB2 ; 3CQA ; 3CRG ; 3CRH ; 3CRI ; 3CU1 ; 3FGM ; 3FJ8 ; 3FJ9 ; 3FJA ; 3FJB ; 3FJC ; 3FJD ; 3FJE ; 3FJF ; 3FJH ; 3FJI ; 3FJJ ; 3FJK ; 3HOM ; 3JUT ; 3K1X ; 3O3Q ; 3OJ2 ; 3OJM ; 3OJV ; 3UD7 ; 3UD8 ; 3UD9 ; 3UDA ; 4J23 ; 4Q91 ; 4Q9G ; 4Q9P ; 4QAL ; 4QBC ; 4QBV ; 4QC4 ; 4QO3 ; 4XKI ; 4YOL
• Pfam ID: PF00167
• Sequence:
  MAEGEITTFTALTEKFNLPPGNYKKPKLLYCSNGGHFLRILPDGTVDGTRDRSDQHIQLQ
  LSAESVGEVYIKSTETGQYLAMDTDGLLYGSQTPNEECLFLERLEENHYNTYISKKHAEK
  NWFVGLKKNGSCKRGPRTHYGQKAILFLPLPVSSD
• Function: Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as a potent mitogen in vitro. Acts as a ligand for FGFR1 and integrins. Binds to FGFR1 in the presence of heparin leading to FGFR1 dimerization and activation via sequential autophosphorylation on tyrosine residues which act as docking sites for interacting proteins, leading to the activation of several signaling cascades. Binds to integrin ITGAV:ITGB3. Its binding to integrin, subsequent ternary complex formation with integrin and FGFR1, and the recruitment of PTPN11 to the complex are essential for FGF1 signaling. Induces the phosphorylation and activation of FGFR1, FRS2, MAPK3/ERK1, MAPK1/ERK2 and AKT1. Can induce angiogenesis.
• Tissue Specificity: Predominantly expressed in kidney and brain. Detected at much lower levels in heart and skeletal muscle.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  PI3K-Akt sig.ling pathway (hsa04151)
  Hippo sig.ling pathway (hsa04390)
  Regulation of actin cytoskeleton (hsa04810)
  Pathways in cancer (hsa05200)
  Melanoma (hsa05218)
  Breast cancer (hsa05224)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  (FGFR2)
  (FGFR3)
  (FGFR4)
  PIP3 activates AKT signaling (R-HSA-1257604)
  Signaling by activated point mutants of FGFR1 (R-HSA-1839122)
  Signaling by activated point mutants of FGFR3 (R-HSA-1839130)
  FGFR4 ligand binding and activation (R-HSA-190322)
  FGFR1b ligand binding and activation (R-HSA-190370)
  FGFR3b ligand binding and activation (R-HSA-190371)
  FGFR3c ligand binding and activation (R-HSA-190372)
  FGFR1c ligand binding and activation (R-HSA-190373)
  FGFR2c ligand binding and activation (R-HSA-190375)
  FGFR2b ligand binding and activation (R-HSA-190377)
  Activated point mutants of FGFR2 (R-HSA-2033519)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Phospholipase C-mediated cascade (R-HSA-5654219)
  Phospholipase C-mediated cascade (R-HSA-5654221)
  Phospholipase C-mediated cascade (R-HSA-5654227)
  Phospholipase C-mediated cascade (R-HSA-5654228)
  Downstream signaling of activated FGFR1 (R-HSA-5654687)
  SHC-mediated cascade (R-HSA-5654688)
  PI-3K cascade (R-HSA-5654689)
  FRS-mediated FGFR1 signaling (R-HSA-5654693)
  PI-3K cascade (R-HSA-5654695)
  SHC-mediated cascade (R-HSA-5654699)
  FRS-mediated FGFR2 signaling (R-HSA-5654700)
  SHC-mediated cascade (R-HSA-5654704)
  FRS-mediated FGFR3 signaling (R-HSA-5654706)
  PI-3K cascade (R-HSA-5654710)
  FRS-mediated FGFR4 signaling (R-HSA-5654712)
  SHC-mediated cascade (R-HSA-5654719)
  PI-3K cascade (R-HSA-5654720)
  Negative regulation of FGFR1 signaling (R-HSA-5654726)
  Negative regulation of FGFR2 signaling (R-HSA-5654727)
  Negative regulation of FGFR3 signaling (R-HSA-5654732)
  Negative regulation of FGFR4 signaling (R-HSA-5654733)
  Signaling by FGFR2 in disease (R-HSA-5655253)
  Signaling by FGFR1 in disease (R-HSA-5655302)
  Signaling by FGFR3 in disease (R-HSA-5655332)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Signaling by FGFR2 IIIa TM (R-HSA-8851708)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Fibroblast growth factor 1 (FGF1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fibroblast growth factor 1 (FGF1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fibroblast growth factor 1 (FGF1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Fibroblast growth factor 1 (FGF1).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Fibroblast growth factor 1 (FGF1).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Fibroblast growth factor 1 (FGF1).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Fibroblast growth factor 1 (FGF1).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Fibroblast growth factor 1 (FGF1).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Fibroblast growth factor 1 (FGF1).	[3]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Fibroblast growth factor 1 (FGF1).	[3]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Fibroblast growth factor 1 (FGF1).	[10]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Fibroblast growth factor 1 (FGF1).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Fibroblast growth factor 1 (FGF1).	[10]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Fibroblast growth factor 1 (FGF1).	[12]
Puerarin	DMJIMXH	Phase 2	Puerarin increases the expression of Fibroblast growth factor 1 (FGF1).	[10]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 decreases the expression of Fibroblast growth factor 1 (FGF1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fibroblast growth factor 1 (FGF1).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Fibroblast growth factor 1 (FGF1).	[16]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Fibroblast growth factor 1 (FGF1).	[17]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Fibroblast growth factor 1 (FGF1).	[3]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid increases the expression of Fibroblast growth factor 1 (FGF1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Fibroblast growth factor 1 (FGF1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Fibroblast growth factor 1 (FGF1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the secretion of Fibroblast growth factor 1 (FGF1).	[11]
TRANSTORINE	DMP4T87	Investigative	TRANSTORINE decreases the secretion of Fibroblast growth factor 1 (FGF1).	[18]
Quinolinic Acid	DM8YGOI	Investigative	Quinolinic Acid decreases the secretion of Fibroblast growth factor 1 (FGF1).	[18]

References

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• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [7] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [8] WNT7A/-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer. Oncogene. 2015 Jun;34(26):3452-62. doi: 10.1038/onc.2014.277. Epub 2014 Sep 1.
• [9] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [10] Examining the genomic influence of skin antioxidants in vitro. Mediators Inflamm. 2010;2010.
• [11] The release of fibroblast growth factor-1 from melanoma cells requires copper ions and is mediated by phosphatidylinositol 3-kinase/Akt intracellular signaling pathway. Cancer Lett. 2008 Aug 18;267(1):67-74. doi: 10.1016/j.canlet.2008.03.001. Epub 2008 Apr 8.
• [12] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [13] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [17] Non-nutritional sweeteners effects on endothelial vascular function. Toxicol In Vitro. 2020 Feb;62:104694. doi: 10.1016/j.tiv.2019.104694. Epub 2019 Oct 23.
• [18] Kynurenic acid inhibits the release of the neurotrophic fibroblast growth factor (FGF)-1 and enhances proliferation of glia cells, in vitro. Cell Mol Neurobiol. 2005 Sep;25(6):981-93. doi: 10.1007/s10571-005-8469-y.