Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBM9QIO)

• DOT Name: Fibroblast growth factor 12 (FGF12)
• Synonyms: FGF-12; Fibroblast growth factor homologous factor 1; FHF-1; Myocyte-activating factor
• Gene Name: FGF12
• Related Disease:
  Colorectal carcinoma
  Epilepsy
  Infantile spasm
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Carcinoma of esophagus
  Developmental and epileptic encephalopathy, 47
  Endometritis
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Neoplasm
  Neoplasm of esophagus
  Ventricular tachycardia
  West syndrome
  Acute myelogenous leukaemia
  Autosomal dominant prognathism
  Squamous cell carcinoma
  Undetermined early-onset epileptic encephalopathy
  Brugada syndrome
  Prostate cancer
  Prostate carcinoma
• UniProt ID: FGF12_HUMAN
• PDB ID: 1Q1U; 4JQ0
• Pfam ID: PF00167
• Sequence:
  MAAAIASSLIRQKRQARESNSDRVSASKRRSSPSKDGRSLCERHVLGVFSKVRFCSGRKR
  PVRRRPEPQLKGIVTRLFSQQGYFLQMHPDGTIDGTKDENSDYTLFNLIPVGLRVVAIQG
  VKASLYVAMNGEGYLYSSDVFTPECKFKESVFENYYVIYSSTLYRQQESGRAWFLGLNKE
  GQIMKGNRVKKTKPSSHFVPKPIEVCMYREPSLHEIGEKQGRSRKSSGTPTMNGGKVVNQ
  DST
• Function: Involved in nervous system development and function. Involved in the positive regulation of voltage-gated sodium channel activity. Promotes neuronal excitability by elevating the voltage dependence of neuronal sodium channel SCN8A fast inactivation.
• Tissue Specificity: Brain, eye and testis; highly expressed in embryonic retina, olfactory epithelium, olfactory bulb, and in a segmental pattern of the body wall; in adult olfactory bulb, less in cerebellum, deep cerebellar nuclei, cortex and multiple midbrain structures.
• Reactome Pathway: Phase 0 - rapid depolarisation (R-HSA-5576892)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Epilepsy	DISBB28L	Definitive	Genetic Variation	[2]
Infantile spasm	DISZSKDG	Definitive	Autosomal dominant	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Developmental and epileptic encephalopathy, 47	DISDZPIO	Strong	Autosomal dominant	[6]
Endometritis	DISHGJ6G	Strong	Biomarker	[7]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[4]
Ventricular tachycardia	DISIBXJ3	Strong	Altered Expression	[8]
West syndrome	DISLIAU9	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[9]
Autosomal dominant prognathism	DIS2G3FF	moderate	Genetic Variation	[10]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[11]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[6]
Brugada syndrome	DISSGN0E	Limited	Biomarker	[12]
Prostate cancer	DISF190Y	Limited	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[13]

9 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 12 (FGF12).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fibroblast growth factor 12 (FGF12).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fibroblast growth factor 12 (FGF12).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Fibroblast growth factor 12 (FGF12).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Fibroblast growth factor 12 (FGF12).	[18]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Fibroblast growth factor 12 (FGF12).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Fibroblast growth factor 12 (FGF12).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fibroblast growth factor 12 (FGF12).	[21]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Fibroblast growth factor 12 (FGF12).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Fibroblast growth factor 12 (FGF12).	[22]

References

• [1] Identification of novel DNA methylation markers in colorectal cancer using MIRA-based microarrays.Oncol Rep. 2012 Jul;28(1):99-104. doi: 10.3892/or.2012.1779. Epub 2012 Apr 23.
• [2] Entire FGF12 duplication by complex chromosomal rearrangements associated with West syndrome.J Hum Genet. 2019 Oct;64(10):1005-1014. doi: 10.1038/s10038-019-0641-1. Epub 2019 Jul 16.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Identification and Validation of Fibroblast Growth Factor 12 Gene as a Novel Potential Biomarker in Esophageal Cancer Using Cancer Genomic Datasets.OMICS. 2017 Oct;21(10):616-631. doi: 10.1089/omi.2017.0116.
• [5] Fibroblast Growth Factor 12 Is a Novel Regulator of Vascular Smooth Muscle Cell Plasticity and Fate.Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1928-36. doi: 10.1161/ATVBAHA.116.308017. Epub 2016 Jul 28.
• [6] Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy. Neurology. 2016 Jun 7;86(23):2162-70. doi: 10.1212/WNL.0000000000002752. Epub 2016 May 4.
• [7] Genomic breeding values, SNP effects and gene identification for disease traits in cow training sets.Anim Genet. 2018 Jun;49(3):178-192. doi: 10.1111/age.12661. Epub 2018 Apr 6.
• [8] De Novo FGF12 (Fibroblast Growth Factor 12) Functional Variation Is Potentially Associated With Idiopathic Ventricular Tachycardia.J Am Heart Assoc. 2017 Aug 3;6(8):e006130. doi: 10.1161/JAHA.117.006130.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] Targeted sequencing in FGF/FGFR genes and association analysis of variants for mandibular prognathism.Medicine (Baltimore). 2017 Jun;96(25):e7240. doi: 10.1097/MD.0000000000007240.
• [11] Identification of novel candidate target genes, including EPHB3, MASP1 and SST at 3q26.2-q29 in squamous cell carcinoma of the lung.BMC Cancer. 2009 Jul 16;9:237. doi: 10.1186/1471-2407-9-237.
• [12] FGF12 is a candidate Brugada syndrome locus.Heart Rhythm. 2013 Dec;10(12):1886-94. doi: 10.1016/j.hrthm.2013.09.064. Epub 2013 Oct 4.
• [13] Identification of Novel Epigenetic Markers of Prostate Cancer by NotI-Microarray Analysis.Dis Markers. 2015;2015:241301. doi: 10.1155/2015/241301. Epub 2015 Sep 28.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006 Oct;33(7):875-82. doi: 10.1016/j.nucmedbio.2006.07.004.
• [16] 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.
• [17] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [18] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [19] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [20] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [21] 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.
• [22] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [23] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.