Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4SQMLQ)

• DOT Name: Interferon-related developmental regulator 1 (IFRD1)
• Synonyms: Nerve growth factor-inducible protein PC4
• Gene Name: IFRD1
• Related Disease:
  Cerebellar ataxia
  Colon cancer
  Colon carcinoma
  Coronary atherosclerosis
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Myocardial ischemia
  Nasal polyp
  Neoplasm
  Non-small-cell lung cancer
  Osteoporosis
  Peripheral neuropathy
  Pulmonary disease
  Stomach cancer
  Cystic fibrosis
  Inflammation
  Spinocerebellar ataxia type 18
  Adult respiratory distress syndrome
  Amyotrophic lateral sclerosis
  Asthma
• UniProt ID: IFRD1_HUMAN
• Pfam ID: PF05004 ; PF04836
• Sequence:
  MPKNKKRNTPHRGSSAGGGGSGAAAATAATAGGQHRNVQPFSDEDASIETMSHCSGYSDP
  SSFAEDGPEVLDEEGTQEDLEYKLKGLIDLTLDKSAKTRQAALEGIKNALASKMLYEFIL
  ERRMTLTDSIERCLKKGKSDEQRAAAALASVLCIQLGPGIESEEILKTLGPILKKIICDG
  SASMQARQTCATCFGVCCFIATDDITELYSTLECLENIFTKSYLKEKDTTVICSTPNTVL
  HISSLLAWTLLLTICPINEVKKKLEMHFHKLPSLLSCDDVNMRIAAGESLALLFELARGI
  ESDFFYEDMESLTQMLRALATDGNKHRAKVDKRKQRSVFRDVLRAVEERDFPTETIKFGP
  ERMYIDCWVKKHTYDTFKEVLGSGMQYHLQSNEFLRNVFELGPPVMLDAATLKTMKISRF
  ERHLYNSAAFKARTKARSKCRDKRADVGEFF
• Function: Could play a role in regulating gene activity in the proliferative and/or differentiative pathways induced by NGF. May be an autocrine factor that attenuates or amplifies the initial ligand-induced signal.
• Tissue Specificity: Expressed in a variety of tissues.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[1]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[2]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[3]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[5]
Myocardial ischemia	DISFTVXF	Strong	Genetic Variation	[3]
Nasal polyp	DISLP3XE	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[7]
Osteoporosis	DISF2JE0	Strong	Biomarker	[8]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[1]
Pulmonary disease	DIS6060I	Strong	Biomarker	[6]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[4]
Cystic fibrosis	DIS2OK1Q	moderate	Genetic Variation	[6]
Inflammation	DISJUQ5T	moderate	Biomarker	[9]
Spinocerebellar ataxia type 18	DIS9KIX3	Supportive	Autosomal dominant	[10]
Adult respiratory distress syndrome	DISIJV47	Limited	Biomarker	[11]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[12]
Asthma	DISW9QNS	Limited	Biomarker	[13]

29 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 Interferon-related developmental regulator 1 (IFRD1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Interferon-related developmental regulator 1 (IFRD1).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Interferon-related developmental regulator 1 (IFRD1).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Interferon-related developmental regulator 1 (IFRD1).	[22]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Interferon-related developmental regulator 1 (IFRD1).	[23]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[24]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[18]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[25]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[26]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[27]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[28]
Ampicillin	DMHWE7P	Approved	Ampicillin decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[29]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[30]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[31]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[32]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[37]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[38]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[28]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[39]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Interferon-related developmental regulator 1 (IFRD1).	[40]
Bilirubin	DMI0V4O	Investigative	Bilirubin increases the expression of Interferon-related developmental regulator 1 (IFRD1).	[41]

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 Interferon-related developmental regulator 1 (IFRD1).	[33]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Interferon-related developmental regulator 1 (IFRD1).	[34]

References

• [1] Identification of IFRD1 variant in a Han Chinese family with autosomal dominant hereditary spastic paraplegia associated with peripheral neuropathy and ataxia.J Hum Genet. 2018 Apr;63(4):521-524. doi: 10.1038/s10038-017-0394-7. Epub 2018 Jan 23.
• [2] Increased IFRD1 Expression in Human Colon Cancers Predicts Reduced Patient Survival.Dig Dis Sci. 2017 Dec;62(12):3460-3467. doi: 10.1007/s10620-017-4819-0. Epub 2017 Nov 1.
• [3] Myocardial immediate early gene activation after cardiopulmonary bypass with cardiac ischemia-reperfusion.Ann Thorac Surg. 2002 Jan;73(1):156-62. doi: 10.1016/s0003-4975(01)03303-3.
• [4] IFRD1 polymorphisms and gastric cancer risk in a Chinese population.Med Oncol. 2014 Sep;31(9):135. doi: 10.1007/s12032-014-0135-0. Epub 2014 Jul 30.
• [5] The human homolog of the rodent immediate early response genes, PC4 and TIS7, resides in the lung cancer tumor suppressor gene region on chromosome 3p21.Hum Genet. 1997 Mar;99(3):334-41. doi: 10.1007/s004390050368.
• [6] IFRD1 gene polymorphisms are associated with nasal polyposis in cystic fibrosis patients.Rhinology. 2015 Dec;53(4):359-64. doi: 10.4193/Rhino14.229.
• [7] Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer.Cancer Gene Ther. 2012 Oct;19(10):690-6. doi: 10.1038/cgt.2012.52. Epub 2012 Aug 24.
• [8] A Novel Diterpenoid Suppresses Osteoclastogenesis and Promotes Osteogenesis by Inhibiting Ifrd1-Mediated and IB-Mediated p65 Nuclear Translocation.J Bone Miner Res. 2018 Apr;33(4):667-678. doi: 10.1002/jbmr.3334. Epub 2018 Feb 21.
• [9] Reduced expression of Tis7/IFRD1 protein in murine and human cystic fibrosis airway epithelial cell models homozygous for the F508del-CFTR mutation.Biochem Biophys Res Commun. 2011 Aug 5;411(3):471-6. doi: 10.1016/j.bbrc.2011.06.104. Epub 2011 Jun 24.
• [10] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [11] MicroRNA and mRNA expression profiling in rat acute respiratory distress syndrome.BMC Med Genomics. 2014 Jul 28;7:46. doi: 10.1186/1755-8794-7-46.
• [12] ALS blood expression profiling identifies new biomarkers, patient subgroups, and evidence for neutrophilia and hypoxia.J Transl Med. 2019 May 22;17(1):170. doi: 10.1186/s12967-019-1909-0.
• [13] Uncovering potential key genes associated with the pathogenesis of asthma: A microarray analysis of asthma-relevant tissues.Allergol Immunopathol (Madr). 2017 Mar-Apr;45(2):152-159. doi: 10.1016/j.aller.2016.08.007. Epub 2016 Nov 11.
• [14] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [19] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [20] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [21] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [22] 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.
• [23] 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.
• [24] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [25] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [26] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [27] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [28] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [29] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [32] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [33] 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.
• [34] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [35] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [36] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [37] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [38] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [39] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [40] 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.
• [41] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.