Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRIVK9Y)

• DOT Name: Follistatin (FST)
• Synonyms: FS; Activin-binding protein
• Gene Name: FST
• UniProt ID: FST_HUMAN
• PDB ID: 2B0U; 2P6A; 3HH2; 5JHW
• Pfam ID: PF09289 ; PF21333 ; PF07648
• Sequence:
  MVRARHQPGGLCLLLLLLCQFMEDRSAQAGNCWLRQAKNGRCQVLYKTELSKEECCSTGR
  LSTSWTEEDVNDNTLFKWMIFNGGAPNCIPCKETCENVDCGPGKKCRMNKKNKPRCVCAP
  DCSNITWKGPVCGLDGKTYRNECALLKARCKEQPELEVQYQGRCKKTCRDVFCPGSSTCV
  VDQTNNAYCVTCNRICPEPASSEQYLCGNDGVTYSSACHLRKATCLLGRSIGLAYEGKCI
  KAKSCEDIQCTGGKKCLWDFKVGRGRCSLCDELCPDSKSDEPVCASDNATYASECAMKEA
  ACSSGVLLEVKHSGSCNSISEDTEEEEEDEDQDYSFPISSILEW
• Function: Binds directly to activin and functions as an activin antagonist. Specific inhibitor of the biosynthesis and secretion of pituitary follicle stimulating hormone (FSH).
• Tissue Specificity: Isoform 1 is the predominant isoform in serum but is undetectable in follicular fluid. In the embryo, strong expression is seen in the palatal epithelia, including the medial edge epithelial and midline epithelial seam of the palatal shelves. Less pronounced expression is also seen throughout the palatal shelf and tongue mesenchyme .
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway: Antagonism of Activin by Follistatin (R-HSA-2473224)

Molecular Interaction Atlas (MIA) of This DOT

39 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 Follistatin (FST).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Follistatin (FST).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Follistatin (FST).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Follistatin (FST).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Follistatin (FST).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Follistatin (FST).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Follistatin (FST).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Follistatin (FST).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Follistatin (FST).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Follistatin (FST).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Follistatin (FST).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Follistatin (FST).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Follistatin (FST).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Follistatin (FST).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Follistatin (FST).	[15]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Follistatin (FST).	[8]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Follistatin (FST).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Follistatin (FST).	[17]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Follistatin (FST).	[18]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Follistatin (FST).	[19]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Follistatin (FST).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Follistatin (FST).	[21]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Follistatin (FST).	[22]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Follistatin (FST).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Follistatin (FST).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Follistatin (FST).	[25]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Follistatin (FST).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Follistatin (FST).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Follistatin (FST).	[28]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Follistatin (FST).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Follistatin (FST).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Follistatin (FST).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Follistatin (FST).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Follistatin (FST).	[34]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Follistatin (FST).	[35]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Follistatin (FST).	[36]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Follistatin (FST).	[37]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Follistatin (FST).	[38]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Follistatin (FST).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Follistatin (FST).	[30]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] ERE-independent ERalpha target genes differentially expressed in human breast tumors. Mol Cell Endocrinol. 2005 Dec 21;245(1-2):53-9. doi: 10.1016/j.mce.2005.10.003. Epub 2005 Nov 17.
• [9] 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.
• [10] Novel functional view of the crocidolite asbestos-treated A549 human lung epithelial transcriptome reveals an intricate network of pathways with opposing functions. BMC Genomics. 2008 Aug 7;9:376.
• [11] 1,25-dihydroxyvitamin D3 stimulates activin A production to fine-tune osteoblast-induced mineralization. J Cell Physiol. 2013 Nov;228(11):2167-74. doi: 10.1002/jcp.24388.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [15] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [16] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [17] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [18] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [19] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [20] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
• [23] Resveratrol inhibits pancreatic cancer cell proliferation through transcriptional induction of macrophage inhibitory cytokine-1. J Surg Res. 2007 Apr;138(2):163-9. doi: 10.1016/j.jss.2006.05.037. Epub 2007 Jan 25.
• [24] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [25] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [26] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [27] Gene expression profiling of A549 cells exposed to Milan PM2.5. Toxicol Lett. 2012 Mar 7;209(2):136-45.
• [28] BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget. 2013 Nov;4(11):2080-95.
• [29] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [30] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [35] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [36] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [37] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [38] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [39] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.