Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8HZ3ZL)

• DOT Name: Fibroblast growth factor receptor-like 1 (FGFRL1)
• Synonyms: FGF receptor-like protein 1; FGF homologous factor receptor; FGFR-like protein; Fibroblast growth factor receptor 5; FGFR-5
• Gene Name: FGFRL1
• Related Disease:
  Ovarian neoplasm
  Advanced cancer
  Bladder cancer
  Congenital diaphragmatic hernia
  Craniosynostosis
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Hereditary hemochromatosis
  Malignant soft tissue neoplasm
  Neoplasm
  Ovarian cancer
  Sarcoma
  Squamous cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Wolf-Hirschhorn syndrome
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Osteosarcoma
• UniProt ID: FGRL1_HUMAN
• Pfam ID: PF07679 ; PF13927
• Sequence:
  MTPSPLLLLLLPPLLLGAFPPAAAARGPPKMADKVVPRQVARLGRTVRLQCPVEGDPPPL
  TMWTKDGRTIHSGWSRFRVLPQGLKVKQVEREDAGVYVCKATNGFGSLSVNYTLVVLDDI
  SPGKESLGPDSSSGGQEDPASQQWARPRFTQPSKMRRRVIARPVGSSVRLKCVASGHPRP
  DITWMKDDQALTRPEAAEPRKKKWTLSLKNLRPEDSGKYTCRVSNRAGAINATYKVDVIQ
  RTRSKPVLTGTHPVNTTVDFGGTTSFQCKVRSDVKPVIQWLKRVEYGAEGRHNSTIDVGG
  QKFVVLPTGDVWSRPDGSYLNKLLITRARQDDAGMYICLGANTMGYSFRSAFLTVLPDPK
  PPGPPVASSSSATSLPWPVVIGIPAGAVFILGTLLLWLCQAQKKPCTPAPAPPLPGHRPP
  GTARDRSGDKDLPSLAALSAGPGVGLCEEHGSPAAPQHLLGPGPVAGPKLYPKLYTDIHT
  HTHTHSHTHSHVEGKVHQHIHYQC
• Function: Has a negative effect on cell proliferation.
• Tissue Specificity: Expressed preferentially in cartilaginous tissues and pancreas. Highly expressed in the liver, kidney, heart, brain and skeletal muscle. Weakly expressed in the lung, small intestine and spleen.
• Reactome Pathway: FGFRL1 modulation of FGFR1 signaling (R-HSA-5658623)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ovarian neoplasm	DISEAFTY	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[3]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Biomarker	[4]
Craniosynostosis	DIS6J405	Strong	Genetic Variation	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Hereditary hemochromatosis	DISVG5MT	Strong	Biomarker	[6]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[6]
Sarcoma	DISZDG3U	Strong	Altered Expression	[9]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[7]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[3]
Wolf-Hirschhorn syndrome	DISE4WMQ	Strong	Biomarker	[10]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[11]
Breast cancer	DIS7DPX1	Limited	Biomarker	[12]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[12]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Fibroblast growth factor receptor-like 1 (FGFRL1).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Fibroblast growth factor receptor-like 1 (FGFRL1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Fibroblast growth factor receptor-like 1 (FGFRL1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fibroblast growth factor receptor-like 1 (FGFRL1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Fibroblast growth factor receptor-like 1 (FGFRL1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Fibroblast growth factor receptor-like 1 (FGFRL1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Fibroblast growth factor receptor-like 1 (FGFRL1).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Fibroblast growth factor receptor-like 1 (FGFRL1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Fibroblast growth factor receptor-like 1 (FGFRL1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fibroblast growth factor receptor-like 1 (FGFRL1).	[22]

References

• [1] Aberrant expression of FGFRL1, a novel FGF receptor, in ovarian tumors.Int J Mol Med. 2005 Dec;16(6):1169-73.
• [2] MicroRNA-210 regulates cancer cell proliferation through targeting fibroblast growth factor receptor-like 1 (FGFRL1).J Biol Chem. 2011 Jan 7;286(1):420-8. doi: 10.1074/jbc.M110.170852. Epub 2010 Nov 2.
• [3] MiR-210-3p inhibits the tumor growth and metastasis of bladder cancer via targeting fibroblast growth factor receptor-like 1.Am J Cancer Res. 2017 Aug 1;7(8):1738-1753. eCollection 2017.
• [4] Downregulation of FGFRL1 contributes to the development of the diaphragmatic defect in the nitrofen model of congenital diaphragmatic hernia.Eur J Pediatr Surg. 2011 Jan;21(1):46-9. doi: 10.1055/s-0030-1262853. Epub 2010 Oct 11.
• [5] Characterization of the first FGFRL1 mutation identified in a craniosynostosis patient.Biochim Biophys Acta. 2009 Feb;1792(2):112-21. doi: 10.1016/j.bbadis.2008.11.006. Epub 2008 Nov 13.
• [6] FGFRL1 Promotes Ovarian Cancer Progression by Crosstalk with Hedgehog Signaling.J Immunol Res. 2018 Feb 20;2018:7438608. doi: 10.1155/2018/7438608. eCollection 2018.
• [7] FGFRL1 deficiency reduces motility and tumorigenic potential of cells derived from oesophageal squamous cell carcinomas.Oncol Lett. 2018 Jul;16(1):809-814. doi: 10.3892/ol.2018.8739. Epub 2018 May 18.
• [8] MicroRNA-210 promotes cancer angiogenesis by targeting fibroblast growth factor receptor-like1 in hepatocellular carcinoma.Oncol Rep. 2016 Nov;36(5):2553-2562. doi: 10.3892/or.2016.5129. Epub 2016 Sep 23.
• [9] Canine and human sarcomas exhibit predominant FGFR1 expression and impaired viability after inhibition of signaling.Mol Carcinog. 2015 Sep;54(9):841-52. doi: 10.1002/mc.22155. Epub 2014 Apr 9.
• [10] Prenatal diagnosis of a 1.6-Mb 4p16.3 interstitial microdeletion encompassing FGFRL1 and TACC3 associated with bilateral cleft lip and palate of Wolf-Hirschhorn syndrome facial dysmorphism and short long bones.Taiwan J Obstet Gynecol. 2017 Dec;56(6):821-826. doi: 10.1016/j.tjog.2017.10.021.
• [11] miR-210 promotes human osteosarcoma cell migration and invasion by targeting FGFRL1.Oncol Lett. 2018 Aug;16(2):2229-2236. doi: 10.3892/ol.2018.8939. Epub 2018 Jun 11.
• [12] FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.Br J Cancer. 2014 Feb 18;110(4):1088-100. doi: 10.1038/bjc.2013.769.
• [13] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [14] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [17] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [18] 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.
• [19] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.