Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNU59PT)

• DOT Name: DnaJ homolog subfamily C member 12 (DNAJC12)
• Synonyms: J domain-containing protein 1
• Gene Name: DNAJC12
• Related Disease:
  Gnathodiaphyseal dysplasia
  Hyperphenylalaninemia due to DNAJC12 deficiency
  Intellectual disability
  Advanced cancer
  Attention deficit hyperactivity disorder
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cholestasis
  Gastric cancer
  Parkinsonian disorder
  Stomach cancer
  Dystonia
  Neoplasm
  Rectal carcinoma
• UniProt ID: DJC12_HUMAN
• PDB ID: 2CTQ
• Pfam ID: PF00226
• Sequence:
  MDAILNYRSEDTEDYYTLLGCDELSSVEQILAEFKVRALECHPDKHPENPKAVETFQKLQ
  KAKEILTNEESRARYDHWRRSQMSMPFQQWEALNDSVKTSMHWVVRGKKDLMLEESDKTH
  TTKMENEECNEQRERKKEELASTAEKTEQKEPKPLEKSVSPQNSDSSGFADVNGWHLRFR
  WSKDAPSELLRKFRNYEI
• Tissue Specificity: Expressed at high levels in brain, heart, and testis, and at reduced levels in kidney and stomach.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gnathodiaphyseal dysplasia	DISTWRZO	Definitive	Biomarker	[1]
Hyperphenylalaninemia due to DNAJC12 deficiency	DIS7CYDN	Definitive	Autosomal recessive	[2]
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
Cholestasis	DISDJJWE	Strong	Biomarker	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[8]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Dystonia	DISJLFGW	moderate	Genetic Variation	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[10]
Rectal carcinoma	DIS8FRR7	Limited	Altered Expression	[10]

21 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 DnaJ homolog subfamily C member 12 (DNAJC12).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[20]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[21]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[22]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[23]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[24]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[29]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DnaJ homolog subfamily C member 12 (DNAJC12).	[31]

References

• [1] DNAJC12-associated developmental delay, movement disorder, and mild hyperphenylalaninemia identified by whole-exome sequencing re-analysis.Eur J Hum Genet. 2018 Dec;26(12):1867-1870. doi: 10.1038/s41431-018-0237-9. Epub 2018 Aug 23.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] RNA sequencing reveals upregulation of a transcriptomic program associated with stemness in metastatic prostate cancer cells selected for taxane resistance.Oncotarget. 2018 Jul 13;9(54):30363-30384. doi: 10.18632/oncotarget.25744. eCollection 2018 Jul 13.
• [4] Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability.J Med Genet. 2017 Aug 9:jmedgenet-2017-104875. doi: 10.1136/jmedgenet-2017-104875. Online ahead of print.
• [5] JDP1 (DNAJC12/Hsp40) expression in breast cancer and its association with estrogen receptor status.Int J Mol Med. 2006 Feb;17(2):363-7.
• [6] Classification of Cholestatic and Necrotic Hepatotoxicants Using Transcriptomics on Human Precision-Cut Liver Slices.Chem Res Toxicol. 2016 Mar 21;29(3):342-51. doi: 10.1021/acs.chemrestox.5b00491. Epub 2016 Mar 9.
• [7] Increased Expression of DNAJC12 is Associated with Aggressive Phenotype of Gastric Cancer.Ann Surg Oncol. 2019 Mar;26(3):836-844. doi: 10.1245/s10434-018-07149-y. Epub 2019 Jan 7.
• [8] DNAJC proteins and pathways to parkinsonism.FEBS J. 2019 Aug;286(16):3080-3094. doi: 10.1111/febs.14936. Epub 2019 Jun 20.
• [9] DNAJC12 mutation is rare in Chinese Han population with Parkinson's disease.Neurobiol Aging. 2018 Aug;68:159.e1-159.e2. doi: 10.1016/j.neurobiolaging.2018.04.012. Epub 2018 May 2.
• [10] Overexpression of DNAJC12 predicts poor response to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer.Exp Mol Pathol. 2015 Jun;98(3):338-45. doi: 10.1016/j.yexmp.2015.03.029. Epub 2015 Mar 21.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [14] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [15] 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.
• [16] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [22] 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.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [25] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [26] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [27] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [30] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [31] 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.