Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFU0IUW)

• DOT Name: Fibroblast growth factor 8 (FGF8)
• Synonyms: FGF-8; Androgen-induced growth factor; AIGF; Heparin-binding growth factor 8; HBGF-8
• Gene Name: FGF8
• Related Disease:
  Hypogonadotropic hypogonadism 6 with or without anosmia
  Holoprosencephaly
  Hypogonadotropic hypogonadism
  Kallmann syndrome
• UniProt ID: FGF8_HUMAN
• PDB ID: 2FDB
• Pfam ID: PF00167
• Sequence:
  MGSPRSALSCLLLHLLVLCLQAQEGPGRGPALGRELASLFRAGREPQGVSQQHVREQSLV
  TDQLSRRLIRTYQLYSRTSGKHVQVLANKRINAMAEDGDPFAKLIVETDTFGSRVRVRGA
  ETGLYICMNKKGKLIAKSNGKGKDCVFTEIVLENNYTALQNAKYEGWYMAFTRKGRPRKG
  SKTRQHQREVHFMKRLPRGHHTTEQSLRFEFLNYPPFTRSLRGSQRTWAPEPR
• Function: Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration. Required for normal brain, eye, ear and limb development during embryogenesis. Required for normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Plays a role in neurite outgrowth in hippocampal cells.
• 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)
  Regulation of actin cytoskeleton (hsa04810)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Melanoma (hsa05218)
  Breast cancer (hsa05224)
  Gastric cancer (hsa05226)
• Reactome Pathway: Formation of the posterior neural plate (R-HSA-9832991)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadotropic hypogonadism 6 with or without anosmia	DISXWNNI	Strong	Autosomal dominant	[1]
Holoprosencephaly	DISR35EC	Supportive	Autosomal recessive	[2]
Hypogonadotropic hypogonadism	DIS8JSKR	Supportive	Autosomal dominant	[3]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[3]

2 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 8 (FGF8).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fibroblast growth factor 8 (FGF8).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fibroblast growth factor 8 (FGF8).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Fibroblast growth factor 8 (FGF8).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Fibroblast growth factor 8 (FGF8).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Fibroblast growth factor 8 (FGF8).	[8]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Fibroblast growth factor 8 (FGF8).	[9]
Thalidomide	DM70BU5	Approved	Thalidomide increases the expression of Fibroblast growth factor 8 (FGF8).	[10]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Fibroblast growth factor 8 (FGF8).	[10]
Abacavir	DMMN36E	Approved	Abacavir increases the expression of Fibroblast growth factor 8 (FGF8).	[10]
Dabigatran	DMDI6R4	Approved	Dabigatran increases the expression of Fibroblast growth factor 8 (FGF8).	[10]
Ramelteon	DM7IW9J	Approved	Ramelteon decreases the expression of Fibroblast growth factor 8 (FGF8).	[10]
Dolutegravir	DMCZGRE	Approved	Dolutegravir increases the expression of Fibroblast growth factor 8 (FGF8).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Fibroblast growth factor 8 (FGF8).	[8]
CHIR-99021	DMB8MNU	Patented	CHIR-99021 increases the expression of Fibroblast growth factor 8 (FGF8).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Fibroblast growth factor 8 (FGF8).	[13]
Forskolin	DM6ITNG	Investigative	Forskolin increases the activity of Fibroblast growth factor 8 (FGF8).	[14]
Hydroxyacetic acid	DMQFBH6	Investigative	Hydroxyacetic acid decreases the expression of Fibroblast growth factor 8 (FGF8).	[10]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Recent advances in understanding inheritance of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):258-269. doi: 10.1002/ajmg.c.31619. Epub 2018 May 22.
• [3] Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest. 2008 Aug;118(8):2822-31. doi: 10.1172/JCI34538.
• [4] 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.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [10] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [11] Dolutegravir Impairs Stem Cell-Based 3D Morphogenesis Models in a Manner Dependent on Dose and Timing of Exposure: An Implication for Its Developmental Toxicity. Toxicol Sci. 2021 Nov 24;184(2):191-203. doi: 10.1093/toxsci/kfab112.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Forskolin cooperating with growth factor on generation of dopaminergic neurons from human fetal mesencephalic neural progenitor cells. Neurosci Lett. 2004 May 20;362(2):117-21. doi: 10.1016/j.neulet.2004.03.007.