Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK0PG7R)

• DOT Name: NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2)
• Synonyms: NADH-ubiquinone oxidoreductase MLRQ subunit homolog; NUOMS
• Gene Name: NDUFA4L2
• Related Disease:
  Advanced cancer
  Clear cell renal carcinoma
  Colorectal carcinoma
  Hepatocellular carcinoma
  Intervertebral disc degeneration
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Neuroblastoma
  Rheumatoid arthritis
• UniProt ID: NUA4L_HUMAN
• Pfam ID: PF06522
• Sequence:
  MAGASLGARFYRQIKRHPGIIPMIGLICLGMGSAALYLLRLALRSPDVCWDRKNNPEPWN
  RLSPNDQYKFLAVSTDYKKLKKDRPDF
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Thermogenesis (hsa04714)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• BioCyc Pathway: MetaCyc:G66-33023-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Intervertebral disc degeneration	DISG3AIM	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[7]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[13]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[8]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[8]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[8]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2).	[16]

References

• [1] NDUFA4L2 is associated with clear cell renal cell carcinoma malignancy and is regulated by ELK1.PeerJ. 2017 Nov 17;5:e4065. doi: 10.7717/peerj.4065. eCollection 2017.
• [2] Integrated multi-omics characterization reveals a distinctive metabolic signature and the role of NDUFA4L2 in promoting angiogenesis, chemoresistance, and mitochondrial dysfunction in clear cell renal cell carcinoma.Aging (Albany NY). 2018 Dec 11;10(12):3957-3985. doi: 10.18632/aging.101685.
• [3] Overexpression of NDUFA4L2 is associated with poor prognosis in patients with colorectal cancer.ANZ J Surg. 2017 Dec;87(12):E251-E255. doi: 10.1111/ans.13617. Epub 2016 May 25.
• [4] NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma.Clin Cancer Res. 2016 Jun 15;22(12):3105-17. doi: 10.1158/1078-0432.CCR-15-1987. Epub 2016 Jan 27.
• [5] Mitochondrial NDUFA4L2 attenuates the apoptosis of nucleus pulposus cells induced by oxidative stress via the inhibition of mitophagy.Exp Mol Med. 2019 Nov 18;51(11):1-16. doi: 10.1038/s12276-019-0331-2.
• [6] Mitochondrial NDUFA4L2 protein promotes the vitality of lung cancer cells by repressing oxidative stress.Thorac Cancer. 2019 Apr;10(4):676-685. doi: 10.1111/1759-7714.12984. Epub 2019 Feb 2.
• [7] NDUFA4L2 expression predicts poor prognosis in clear cell renal cell carcinoma patients.Ren Fail. 2016 Sep;38(8):1199-205. doi: 10.1080/0886022X.2016.1208517. Epub 2016 Jul 25.
• [8] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [11] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [14] 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.
• [15] 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.
• [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] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.