Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY8004K)

• DOT Name: Transcription regulator protein BACH1 (BACH1)
• Synonyms: BTB and CNC homolog 1; HA2303
• Gene Name: BACH1
• UniProt ID: BACH1_HUMAN
• PDB ID: 2IHC
• Pfam ID: PF00651 ; PF03131
• Sequence:
  MSLSENSVFAYESSVHSTNVLLSLNDQRKKDVLCDVTIFVEGQRFRAHRSVLAACSSYFH
  SRIVGQADGELNITLPEEVTVKGFEPLIQFAYTAKLILSKENVDEVCKCVEFLSVHNIEE
  SCFQFLKFKFLDSTADQQECPRKKCFSSHCQKTDLKLSLLDQRDLETDEVEEFLENKNVQ
  TPQCKLRRYQGNAKASPPLQDSASQTYESMCLEKDAALALPSLCPKYRKFQKAFGTDRVR
  TGESSVKDIHASVQPNERSENECLGGVPECRDLQVMLKCDESKLAMEPEETKKDPASQCP
  TEKSEVTPFPHNSSIDPHGLYSLSLLHTYDQYGDLNFAGMQNTTVLTEKPLSGTDVQEKT
  FGESQDLPLKSDLGTREDSSVASSDRSSVEREVAEHLAKGFWSDICSTDTPCQMQLSPAV
  AKDGSEQISQKRSECPWLGIRISESPEPGQRTFTTLSSVNCPFISTLSTEGCSSNLEIGN
  DDYVSEPQQEPCPYACVISLGDDSETDTEGDSESCSAREQECEVKLPFNAQRIISLSRND
  FQSLLKMHKLTPEQLDCIHDIRRRSKNRIAAQRCRKRKLDCIQNLESEIEKLQSEKESLL
  KERDHILSTLGETKQNLTGLCQKVCKEAALSQEQIQILAKYSAADCPLSFLISEKDKSTP
  DGELALPSIFSLSDRPPAVLPPCARGNSEPGYARGQESQQMSTATSEQAGPAEQCRQSGG
  ISDFCQQMTDKCTTDE
• Function: Transcriptional regulator that acts as a repressor or activator, depending on the context. Binds to NF-E2 DNA binding sites. Plays important roles in coordinating transcription activation and repression by MAFK. Together with MAF, represses the transcription of genes under the control of the NFE2L2 oxidative stress pathway.
• Reactome Pathway:
  Heme signaling (R-HSA-9707616)
  Regulation of BACH1 activity (R-HSA-9708530)
  NFE2L2 regulating anti-oxidant/detoxification enzymes (R-HSA-9818027)
  Regulation of HMOX1 expression and activity (R-HSA-9707587)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Transcription regulator protein BACH1 (BACH1) decreases the response to substance of Doxorubicin.	[23]
Cisplatin	DMRHGI9	Approved	Transcription regulator protein BACH1 (BACH1) affects the response to substance of Cisplatin.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Transcription regulator protein BACH1 (BACH1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transcription regulator protein BACH1 (BACH1).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transcription regulator protein BACH1 (BACH1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transcription regulator protein BACH1 (BACH1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transcription regulator protein BACH1 (BACH1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcription regulator protein BACH1 (BACH1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transcription regulator protein BACH1 (BACH1).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Transcription regulator protein BACH1 (BACH1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Transcription regulator protein BACH1 (BACH1).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription regulator protein BACH1 (BACH1).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Transcription regulator protein BACH1 (BACH1).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Transcription regulator protein BACH1 (BACH1).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Transcription regulator protein BACH1 (BACH1).	[9]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Transcription regulator protein BACH1 (BACH1).	[13]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Transcription regulator protein BACH1 (BACH1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transcription regulator protein BACH1 (BACH1).	[15]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of Transcription regulator protein BACH1 (BACH1).	[16]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Transcription regulator protein BACH1 (BACH1).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transcription regulator protein BACH1 (BACH1).	[18]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Transcription regulator protein BACH1 (BACH1).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Transcription regulator protein BACH1 (BACH1).	[11]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Transcription regulator protein BACH1 (BACH1).	[21]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the expression of Transcription regulator protein BACH1 (BACH1).	[22]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX increases the expression of Transcription regulator protein BACH1 (BACH1).	[11]
CHLORANIL	DMCHGF1	Investigative	CHLORANIL increases the expression of Transcription regulator protein BACH1 (BACH1).	[22]

5 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroquinone	DM6AVR4	Approved	Hydroquinone affects the localization of Transcription regulator protein BACH1 (BACH1).	[12]
Tecfidera	DM2OVDT	Approved	Tecfidera affects the localization of Transcription regulator protein BACH1 (BACH1).	[14]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol affects the localization of Transcription regulator protein BACH1 (BACH1).	[12]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone affects the localization of Transcription regulator protein BACH1 (BACH1).	[12]
Citraconic acid	DMCIM9A	Investigative	Citraconic acid affects the localization of Transcription regulator protein BACH1 (BACH1).	[14]

References

• [1] 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.
• [2] 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.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Inorganic arsenic promotes luminal to basal transition and metastasis of breast cancer. FASEB J. 2020 Dec;34(12):16034-16048. doi: 10.1096/fj.202001192R. Epub 2020 Oct 13.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] miR-155/BACH1 signaling pathway in human lung adenocarcinoma cell death induced by arsenic trioxide. Sichuan Da Xue Xue Bao Yi Xue Ban. 2017 Nov;48(6):828-833.
• [8] Comparison of protective effect of ascorbic acid on redox and endocannabinoid systems interactions in in vitro cultured human skin fibroblasts exposed to UV radiation and hydrogen peroxide. Arch Dermatol Res. 2017 May;309(4):285-303. doi: 10.1007/s00403-017-1729-0. Epub 2017 Mar 11.
• [9] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [10] 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.
• [11] Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol. 2020 Jan;28:101321. doi: 10.1016/j.redox.2019.101321. Epub 2019 Sep 5.
• [12] The electrophilic character of quinones is essential for the suppression of Bach1. Toxicology. 2017 Jul 15;387:17-26.
• [13] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [14] Distinct Nrf2 Signaling Mechanisms of Fumaric Acid Esters and Their Role in Neuroprotection against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Experimental Parkinson's-Like Disease. J Neurosci. 2016 Jun 8;36(23):6332-51. doi: 10.1523/JNEUROSCI.0426-16.2016.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [17] The effects of Phorbol 12-myristate 13-acetate concentration on the expression of miR-155 and miR-125b and their macrophage function-related genes in the U937 cell line. J Toxicol Sci. 2020;45(12):751-761. doi: 10.2131/jts.45.751.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] Differential effects of arsenic species on Nrf2 and Bach1 nuclear localization in cultured hepatocytes. Toxicol Appl Pharmacol. 2021 Feb 15;413:115404. doi: 10.1016/j.taap.2021.115404. Epub 2021 Jan 9.
• [21] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [22] Tetrachlorobenzoquinone induces Nrf2 activation via rapid Bach1 nuclear export/ubiquitination and JNK-P62 signaling. Toxicology. 2016 Jul 1;363-364:48-57. doi: 10.1016/j.tox.2016.07.002. Epub 2016 Jul 5.
• [23] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.