Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG9DUIV)

• DOT Name: Nucleus accumbens-associated protein 2 (NACC2)
• Synonyms: NAC-2; BTB/POZ domain-containing protein 14A; Repressor with BTB domain and BEN domain
• Gene Name: NACC2
• UniProt ID: NACC2_HUMAN
• Pfam ID: PF10523 ; PF00651
• Sequence:
  MSQMLHIEIPNFGNTVLGCLNEQRLLGLYCDVSIVVKGQAFKAHRAVLAASSLYFRDLFS
  GNSKSAFELPGSVPPACFQQILSFCYTGRLTMTASEQLVVMYTAGFLQIQHIVERGTDLM
  FKVSSPHCDSQTAVIEDAGSEPQSPCNQLQPAAAAAAPYVVSPSVPIPLLTRVKHEAMEL
  PPAGPGLAPKRPLETGPRDGVAVAAGAAVAAGTAPLKLPRVSYYGVPSLATLIPGIQQMP
  YPQGERTSPGASSLPTTDSPTSYHNEEDEEDDEAYDTMVEEQYGQMYIKASGSYAVQEKP
  EPVPLESRSCVLIRRDLVALPASLISQIGYRCHPKLYSEGDPGEKLELVAGSGVYITRGQ
  LMNCHLCAGVKHKVLLRRLLATFFDRNTLANSCGTGIRSSTSDPSRKPLDSRVLNAVKLY
  CQNFAPSFKESEMNVIAADMCTNARRVRKRWLPKIKSMLPEGVEMYRTVMGSAAASVPLD
  PEFPPAAAQVFEQRIYAERRGDAATIVALRTDAVNVDLSAAANPAFDAGEEVDGAGSVIQ
  EVAAPEPLPADGQSPPQPFEQGGGGPSRPQTPAAAARRPEGTYAGTL
• Function: Functions as a transcriptional repressor through its association with the NuRD complex. Recruits the NuRD complex to the promoter of MDM2, leading to the repression of MDM2 transcription and subsequent stability of p53/TP53.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Nucleus accumbens-associated protein 2 (NACC2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Nucleus accumbens-associated protein 2 (NACC2).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Nucleus accumbens-associated protein 2 (NACC2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nucleus accumbens-associated protein 2 (NACC2).	[16]

14 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 Nucleus accumbens-associated protein 2 (NACC2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nucleus accumbens-associated protein 2 (NACC2).	[3]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Nucleus accumbens-associated protein 2 (NACC2).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nucleus accumbens-associated protein 2 (NACC2).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Nucleus accumbens-associated protein 2 (NACC2).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Nucleus accumbens-associated protein 2 (NACC2).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Nucleus accumbens-associated protein 2 (NACC2).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Nucleus accumbens-associated protein 2 (NACC2).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Nucleus accumbens-associated protein 2 (NACC2).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Nucleus accumbens-associated protein 2 (NACC2).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Nucleus accumbens-associated protein 2 (NACC2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nucleus accumbens-associated protein 2 (NACC2).	[14]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Nucleus accumbens-associated protein 2 (NACC2).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Nucleus accumbens-associated protein 2 (NACC2).	[17]

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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] 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.
• [15] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [16] 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.
• [17] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.