Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT38BZQQ)

• DOT Name: DnaJ homolog subfamily A member 1 (DNAJA1)
• Synonyms: DnaJ protein homolog 2; HSDJ; Heat shock 40 kDa protein 4; Heat shock protein J2; HSJ-2; Human DnaJ protein 2; hDj-2
• Gene Name: DNAJA1
• Related Disease:
  Intellectual disability
  Oculopharyngeal muscular dystrophy
  Advanced cancer
  Huntington disease
  Kennedy disease
  Colorectal carcinoma
  Autosomal dominant cerebellar ataxia type II
  Complex neurodevelopmental disorder
  Malignant pleural mesothelioma
  Mouth disorder
  Neoplasm
• UniProt ID: DNJA1_HUMAN
• PDB ID: 2LO1; 2M6Y; 6E8M; 8E2O
• Pfam ID: PF00226 ; PF01556 ; PF00684
• Sequence:
  MVKETTYYDVLGVKPNATQEELKKAYRKLALKYHPDKNPNEGEKFKQISQAYEVLSDAKK
  RELYDKGGEQAIKEGGAGGGFGSPMDIFDMFFGGGGRMQRERRGKNVVHQLSVTLEDLYN
  GATRKLALQKNVICDKCEGRGGKKGAVECCPNCRGTGMQIRIHQIGPGMVQQIQSVCMEC
  QGHGERISPKDRCKSCNGRKIVREKKILEVHIDKGMKDGQKITFHGEGDQEPGLEPGDII
  IVLDQKDHAVFTRRGEDLFMCMDIQLVEALCGFQKPISTLDNRTIVITSHPGQIVKHGDI
  KCVLNEGMPIYRRPYEKGRLIIEFKVNFPENGFLSPDKLSLLEKLLPERKEVEETDEMDQ
  VELVDFDPNQERRRHYNGEAYEDDEHHPRGGVQCQTS
• Function: Co-chaperone for HSPA8/Hsc70. Stimulates ATP hydrolysis, but not the folding of unfolded proteins mediated by HSPA1A (in vitro). Plays a role in protein transport into mitochondria via its role as co-chaperone. Functions as a co-chaperone for HSPA1B and negatively regulates the translocation of BAX from the cytosol to mitochondria in response to cellular stress, thereby protecting cells against apoptosis. Promotes apoptosis in response to cellular stress mediated by exposure to anisomycin or UV.
• Tissue Specificity: Ubiquitous. Isoform 2 is highly expressed in testis and lung, but detected at low levels in thymus, prostate, colon and liver.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway: HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Oculopharyngeal muscular dystrophy	DISF4G07	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Huntington disease	DISQPLA4	Strong	Biomarker	[4]
Kennedy disease	DISXZVM1	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[5]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Limited	Altered Expression	[6]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal recessive	[7]
Malignant pleural mesothelioma	DIST2R60	Limited	Biomarker	[8]
Mouth disorder	DISX82BI	Limited	Biomarker	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]

28 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 DnaJ homolog subfamily A member 1 (DNAJA1).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[21]
Marinol	DM70IK5	Approved	Marinol decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[22]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[24]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[25]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[26]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[21]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[27]
Gallium nitrate	DMF9O6B	Approved	Gallium nitrate increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[28]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[29]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[31]
Arecoline	DMFJZK3	Phase 1	Arecoline increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[35]
Celastrol	DMWQIJX	Preclinical	Celastrol increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[36]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[38]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[39]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of DnaJ homolog subfamily A member 1 (DNAJA1).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of DnaJ homolog subfamily A member 1 (DNAJA1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of DnaJ homolog subfamily A member 1 (DNAJA1).	[30]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DnaJ homolog subfamily A member 1 (DNAJA1).	[32]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DnaJ homolog subfamily A member 1 (DNAJA1).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DnaJ homolog subfamily A member 1 (DNAJA1).	[37]

References

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• [2] Mammalian, yeast, bacterial, and chemical chaperones reduce aggregate formation and death in a cell model of oculopharyngeal muscular dystrophy.J Biol Chem. 2002 Apr 5;277(14):12263-9. doi: 10.1074/jbc.M109633200. Epub 2002 Jan 16.
• [3] Inhibition of mutant Kras and p53-driven pancreatic carcinogenesis by atorvastatin: Mainly via targeting of the farnesylated DNAJA1 in chaperoning mutant p53.Mol Carcinog. 2019 Nov;58(11):2052-2064. doi: 10.1002/mc.23097. Epub 2019 Aug 9.
• [4] Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease.Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2898-903. doi: 10.1073/pnas.97.6.2898.
• [5] KNK437 restricts the growth and metastasis of colorectal cancer via targeting DNAJA1/CDC45 axis.Oncogene. 2020 Jan;39(2):249-261. doi: 10.1038/s41388-019-0978-0. Epub 2019 Sep 2.
• [6] Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts.Eur J Hum Genet. 2014 Dec;22(12):1369-75. doi: 10.1038/ejhg.2014.39. Epub 2014 Mar 26.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] Genomic events associated with progression of pleural malignant mesothelioma.Int J Cancer. 2009 Feb 1;124(3):589-99. doi: 10.1002/ijc.23949.
• [9] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Alteration of genomic responses to doxorubicin and prevention of MDR in breast cancer cells by a polymer excipient: pluronic P85. Mol Pharm. 2006 Mar-Apr;3(2):113-23.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [18] 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.
• [19] Darinaparsin induces a unique cellular response and is active in an arsenic trioxide-resistant myeloma cell line. Mol Cancer Ther. 2009 May;8(5):1197-206.
• [20] 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.
• [21] 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.
• [22] Gene expression changes in human small airway epithelial cells exposed to Delta9-tetrahydrocannabinol. Toxicol Lett. 2005 Aug 14;158(2):95-107.
• [23] 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.
• [24] 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.
• [25] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [26] Survival of retinal pigment epithelium after exposure to prolonged oxidative injury: a detailed gene expression and cellular analysis. Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3767-77.
• [27] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [28] Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells. Free Radic Biol Med. 2008 Sep 15;45(6):763-72.
• [29] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [30] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] 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.
• [33] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [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] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [36] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [37] Bisphenol-A impairs cellular function and alters DNA methylation of stress pathway genes in first trimester trophoblast cells. Reprod Toxicol. 2018 Dec;82:72-79.
• [38] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [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] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.