Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2DVJWY)

• DOT Name: Fibroblast growth factor 19 (FGF19)
• Synonyms: FGF-19
• Gene Name: FGF19
• UniProt ID: FGF19_HUMAN
• PDB ID: 1PWA; 2P23; 6KTR; 6NFJ
• Pfam ID: PF00167
• Sequence:
  MRSGCVVVHVWILAGLWLAVAGRPLAFSDAGPHVHYGWGDPIRLRHLYTSGPHGLSSCFL
  RIRADGVVDCARGQSAHSLLEIKAVALRTVAIKGVHSVRYLCMGADGKMQGLLQYSEEDC
  AFEEEIRPDGYNVYRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEEPEDLR
  GHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK
• Function: Involved in the suppression of bile acid biosynthesis through down-regulation of CYP7A1 expression, following positive regulation of the JNK and ERK1/2 cascades. Stimulates glucose uptake in adipocytes. Activity requires the presence of KLB and FGFR4.
• Tissue Specificity: Expressed in fetal brain, cartilage, retina, and adult gall bladder.
• 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)
  Melanoma (hsa05218)
  Breast cancer (hsa05224)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  (FGFR4)
  PIP3 activates AKT signaling (R-HSA-1257604)
  betaKlotho-mediated ligand binding (R-HSA-1307965)
  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)
  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

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Fibroblast growth factor 19 (FGF19).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Fibroblast growth factor 19 (FGF19).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Fibroblast growth factor 19 (FGF19).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Fibroblast growth factor 19 (FGF19).	[4]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Fibroblast growth factor 19 (FGF19).	[5]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Fibroblast growth factor 19 (FGF19).	[6]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Fibroblast growth factor 19 (FGF19).	[7]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Fibroblast growth factor 19 (FGF19).	[8]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid increases the expression of Fibroblast growth factor 19 (FGF19).	[9]
Ritonavir	DMU764S	Approved	Ritonavir increases the expression of Fibroblast growth factor 19 (FGF19).	[10]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of Fibroblast growth factor 19 (FGF19).	[11]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid increases the expression of Fibroblast growth factor 19 (FGF19).	[9]
Clavulanate	DM2FGRT	Approved	Clavulanate increases the expression of Fibroblast growth factor 19 (FGF19).	[13]
Cholic acid	DM7OKQV	Approved	Cholic acid increases the expression of Fibroblast growth factor 19 (FGF19).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Fibroblast growth factor 19 (FGF19).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Fibroblast growth factor 19 (FGF19).	[15]
	DM9CEI5		increases the expression of Fibroblast growth factor 19 (FGF19).	[8]

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 19 (FGF19).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fibroblast growth factor 19 (FGF19).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Fibroblast growth factor 19 (FGF19).	[16]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells. Hepatology. 2011 Feb;53(2):548-57. doi: 10.1002/hep.24047. Epub 2010 Dec 10.
• [3] 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.
• [4] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [5] 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.
• [6] 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.
• [7] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [8] Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR. World J Gastroenterol. 2007 Aug 21;13(31):4230-5. doi: 10.3748/wjg.v13.i31.4230.
• [9] Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures. Toxicol Sci. 2014 Oct;141(2):538-46. doi: 10.1093/toxsci/kfu151. Epub 2014 Jul 23.
• [10] Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. Chem Biol Interact. 2016 Aug 5;255:31-44.
• [11] A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids. J Lipid Res. 2006 Feb;47(2):384-92.
• [12] The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. Biochemistry. 2004 Jan 27;43(3):629-40. doi: 10.1021/bi035320k.
• [13] Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol. 2021 Dec;158:112664. doi: 10.1016/j.fct.2021.112664. Epub 2021 Nov 9.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1. Mol Neurobiol. 2017 Jul;54(5):3798-3812. doi: 10.1007/s12035-016-9898-y. Epub 2016 Jun 7.