Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZKO6ZN)

• DOT Name: Neuronal PAS domain-containing protein 1 (NPAS1)
• Synonyms: Neuronal PAS1; Basic-helix-loop-helix-PAS protein MOP5; Class E basic helix-loop-helix protein 11; bHLHe11; Member of PAS protein 5; PAS domain-containing protein 5
• Gene Name: NPAS1
• Related Disease:
  Hepatocellular carcinoma
  Intellectual disability
  Psychotic disorder
  Schizophrenia
• UniProt ID: NPAS1_HUMAN
• Pfam ID: PF00989 ; PF08447
• Sequence:
  MAAPYPGSGGGSEVKCVGGRGASVPWDFLPGLMVKAPSGPCLQAQRKEKSRNAARSRRGK
  ENLEFFELAKLLPLPGAISSQLDKASIVRLSVTYLRLRRFAALGAPPWGLRAAGPPAGLA
  PGRRGPAALVSEVFEQHLGGHILQSLDGFVFALNQEGKFLYISETVSIYLGLSQVEMTGS
  SVFDYIHPGDHSEVLEQLGLRTPTPGPPTPPSVSSSSSSSSSLADTPEIEASLTKVPPSS
  LVQERSFFVRMKSTLTKRGLHVKASGYKVIHVTGRLRAHALGLVALGHTLPPAPLAELPL
  HGHMIVFRLSLGLTILACESRVSDHMDLGPSELVGRSCYQFVHGQDATRIRQSHVDLLDK
  GQVMTGYYRWLQRAGGFVWLQSVATVAGSGKSPGEHHVLWVSHVLSQAEGGQTPLDAFQL
  PASVACEEASSPGPEPTEPEPPTEGKQAAPAENEAPQTQGKRIKVEPGPRETKGSEDSGD
  EDPSSHPATPRPEFTSVIRAGVLKQDPVRPWGLAPPGDPPPTLLHAGFLPPVVRGLCTPG
  TIRYGPAELGLVYPHLQRLGPGPALPEAFYPPLGLPYPGPAGTRLPRKGD
• Function: May control regulatory pathways relevant to schizophrenia and to psychotic illness. May play a role in late central nervous system development by modulating EPO expression in response to cellular oxygen level. Forms a heterodimer that binds core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) leading to transcriptional repression on its target gene TH.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Biomarker	[2]

1 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 1 (NPAS1).	[4]

10 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 Neuronal PAS domain-containing protein 1 (NPAS1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neuronal PAS domain-containing protein 1 (NPAS1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Neuronal PAS domain-containing protein 1 (NPAS1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Neuronal PAS domain-containing protein 1 (NPAS1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neuronal PAS domain-containing protein 1 (NPAS1).	[9]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Neuronal PAS domain-containing protein 1 (NPAS1).	[10]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Neuronal PAS domain-containing protein 1 (NPAS1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Neuronal PAS domain-containing protein 1 (NPAS1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Neuronal PAS domain-containing protein 1 (NPAS1).	[13]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Neuronal PAS domain-containing protein 1 (NPAS1).	[14]

References

• [1] The anti-metastatic effect of 8-MOP on hepatocellular carcinoma is potentiated by the down-regulation of bHLH transcription factor DEC1.Pharmacol Res. 2016 Mar;105:121-33. doi: 10.1016/j.phrs.2016.01.025. Epub 2016 Jan 22.
• [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] Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors.Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13648-53. doi: 10.1073/pnas.0405310101. Epub 2004 Sep 3.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [10] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [11] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [12] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [13] 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.
• [14] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.