Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8D1ILB)

• DOT Name: Neuronal PAS domain-containing protein 3 (NPAS3)
• Synonyms: Neuronal PAS3; Basic-helix-loop-helix-PAS protein MOP6; Class E basic helix-loop-helix protein 12; bHLHe12; Member of PAS protein 6; PAS domain-containing protein 6
• Gene Name: NPAS3
• Related Disease:
  Intellectual disability
  Angelman syndrome
  Astrocytoma
  Bipolar disorder
  Glioblastoma multiforme
  Major depressive disorder
  Malignant glioma
  Mental disorder
  Neoplasm
  Psychotic disorder
  Lung squamous cell carcinoma
  Neurodevelopmental disorder
• UniProt ID: NPAS3_HUMAN
• Pfam ID: PF00989 ; PF08447
• Sequence:
  MAPTKPSFQQDPSRRERITAQHPLPNQSECRKIYRYDGIYCESTYQNLQALRKEKSRDAA
  RSRRGKENFEFYELAKLLPLPAAITSQLDKASIIRLTISYLKMRDFANQGDPPWNLRMEG
  PPPNTSVKVIGAQRRRSPSALAIEVFEAHLGSHILQSLDGFVFALNQEGKFLYISETVSI
  YLGLSQVELTGSSVFDYVHPGDHVEMAEQLGMKLPPGRGLLSQGTAEDGASSASSSSQSE
  TPEPVESTSPSLLTTDNTLERSFFIRMKSTLTKRGVHIKSSGYKVIHITGRLRLRVSLSH
  GRTVPSQIMGLVVVAHALPPPTINEVRIDCHMFVTRVNMDLNIIYCENRISDYMDLTPVD
  IVGKRCYHFIHAEDVEGIRHSHLDLLNKGQCVTKYYRWMQKNGGYIWIQSSATIAINAKN
  ANEKNIIWVNYLLSNPEYKDTPMDIAQLPHLPEKTSESSETSDSESDSKDTSGITEDNEN
  SKSDEKGNQSENSEDPEPDRKKSGNACDNDMNCNDDGHSSSNPDSRDSDDSFEHSDFENP
  KAGEDGFGALGAMQIKVERYVESESDLRLQNCESLTSDSAKDSDSAGEAGAQASSKHQKR
  KKRRKRQKGGSASRRRLSSASSPGGLDAGLVEPPRLLSSPNSASVLKIKTEISEPINFDN
  DSSIWNYPPNREISRNESPYSMTKPPSSEHFPSPQGGGGGGGGGGGLHVAIPDSVLTPPG
  ADGAAARKTQFGASATAALAPVASDPLSPPLSASPRDKHPGNGGGGGGGGGGAGGGGPSA
  SNSLLYTGDLEALQRLQAGNVVLPLVHRVTGTLAATSTAAQRVYTTGTIRYAPAEVTLAM
  QSNLLPNAHAVNFVDVNSPGFGLDPKTPMEMLYHHVHRLNMSGPFGGAVSAASLTQMPAG
  NVFTTAEGLFSTLPFPVYSNGIHAAQTLERKED
• Function: May play a broad role in neurogenesis. May control regulatory pathways relevant to schizophrenia and to psychotic illness.
• Tissue Specificity: Ubiquitously expressed in the adult brain.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Angelman syndrome	DIS4QVXO	Strong	Biomarker	[2]
Astrocytoma	DISL3V18	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[5]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[3]
Mental disorder	DIS3J5R8	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[6]
Lung squamous cell carcinoma	DISXPIBD	Limited	Genetic Variation	[7]
Neurodevelopmental disorder	DIS372XH	Limited	Altered Expression	[8]

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 Neuronal PAS domain-containing protein 3 (NPAS3).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Neuronal PAS domain-containing protein 3 (NPAS3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neuronal PAS domain-containing protein 3 (NPAS3).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Neuronal PAS domain-containing protein 3 (NPAS3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Neuronal PAS domain-containing protein 3 (NPAS3).	[10]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Neuronal PAS domain-containing protein 3 (NPAS3).	[12]
Rofecoxib	DM3P5DA	Approved	Rofecoxib increases the expression of Neuronal PAS domain-containing protein 3 (NPAS3).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Neuronal PAS domain-containing protein 3 (NPAS3).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Neuronal PAS domain-containing protein 3 (NPAS3).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Neuronal PAS domain-containing protein 3 (NPAS3).	[10]

References

• [1] Genome-wide SNP array analysis in patients with features of sotos syndrome.Horm Res Paediatr. 2010;73(4):265-74. doi: 10.1159/000284391. Epub 2010 Mar 9.
• [2] Neuronal PAS Domain Proteins 1 and 3 Are Master Regulators of Neuropsychiatric Risk Genes.Biol Psychiatry. 2017 Aug 1;82(3):213-223. doi: 10.1016/j.biopsych.2017.03.021. Epub 2017 Apr 6.
• [3] NPAS3 demonstrates features of a tumor suppressive role in driving the progression of Astrocytomas.Am J Pathol. 2011 Jul;179(1):462-76. doi: 10.1016/j.ajpath.2011.03.044. Epub 2011 May 19.
• [4] Identification of pathways for bipolar disorder: a meta-analysis.JAMA Psychiatry. 2014 Jun;71(6):657-64. doi: 10.1001/jamapsychiatry.2014.176.
• [5] Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression.Am J Psychiatry. 2010 Oct;167(10):1254-63. doi: 10.1176/appi.ajp.2010.09091335. Epub 2010 Aug 16.
• [6] Association of NPAS3 exonic variation with schizophrenia.Schizophr Res. 2010 Jul;120(1-3):143-9. doi: 10.1016/j.schres.2010.04.002. Epub 2010 May 14.
• [7] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [8] Molecular analysis of NPAS3 functional domains and variants.BMC Mol Biol. 2018 Dec 3;19(1):14. doi: 10.1186/s12867-018-0117-4.
• [9] 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.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] 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.
• [12] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [13] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [14] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [15] 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.
• [16] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.