Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMRT2TS)

• DOT Name: Neuronal PAS domain-containing protein 2 (NPAS2)
• Synonyms: Neuronal PAS2; Basic-helix-loop-helix-PAS protein MOP4; Class E basic helix-loop-helix protein 9; bHLHe9; Member of PAS protein 4; PAS domain-containing protein 4
• Gene Name: NPAS2
• Related Disease:
  Bipolar disorder
  Schizoaffective disorder
  Acute myelogenous leukaemia
  Adenocarcinoma
  Autism
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Chronic fatigue syndrome
  Colorectal carcinoma
  Colorectal neoplasm
  Creutzfeldt Jacob disease
  Depression
  Drug dependence
  Esophageal cancer
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Her2-receptor negative breast cancer
  HER2/NEU overexpressing breast cancer
  High blood pressure
  Lung cancer
  Lung carcinoma
  Lymphoma, non-Hodgkin, familial
  Major depressive disorder
  Mental disorder
  Mood disorder
  Neoplasm
  Neoplasm of esophagus
  Non-hodgkin lymphoma
  Non-small-cell lung cancer
  Osteoarthritis
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Rheumatoid arthritis
  Vitamin D deficiency
  Kidney cancer
  Renal carcinoma
  Small lymphocytic lymphoma
  Advanced cancer
  Anxiety
  Anxiety disorder
  Leiomyosarcoma
  Malignant soft tissue neoplasm
  Malignant tumor of nasopharynx
  Melanoma
  Nasopharyngeal carcinoma
  Sarcoma
  Schizophrenia
• UniProt ID: NPAS2_HUMAN
• Pfam ID: PF00010 ; PF00989 ; PF14598
• Sequence:
  MDEDEKDRAKRASRNKSEKKRRDQFNVLIKELSSMLPGNTRKMDKTTVLEKVIGFLQKHN
  EVSAQTEICDIQQDWKPSFLSNEEFTQLMLEALDGFIIAVTTDGSIIYVSDSITPLLGHL
  PSDVMDQNLLNFLPEQEHSEVYKILSSHMLVTDSPSPEYLKSDSDLEFYCHLLRGSLNPK
  EFPTYEYIKFVGNFRSYNNVPSPSCNGFDNTLSRPCRVPLGKEVCFIATVRLATPQFLKE
  MCIVDEPLEEFTSRHSLEWKFLFLDHRAPPIIGYLPFEVLGTSGYDYYHIDDLELLARCH
  QHLMQFGKGKSCCYRFLTKGQQWIWLQTHYYITYHQWNSKPEFIVCTHSVVSYADVRVER
  RQELALEDPPSEALHSSALKDKGSSLEPRQHFNTLDVGASGLNTSHSPSASSRSSHKSSH
  TAMSEPTSTPTKLMAEASTPALPRSATLPQELPVPGLSQAATMPAPLPSPSSCDLTQQLL
  PQTVLQSTPAPMAQFSAQFSMFQTIKDQLEQRTRILQANIRWQQEELHKIQEQLCLVQDS
  NVQMFLQQPAVSLSFSSTQRPEAQQQLQQRSAAVTQPQLGAGPQLPGQISSAQVTSQHLL
  RESSVISTQGPKPMRSSQLMQSSGRSGSSLVSPFSSATAALPPSLNLTTPASTSQDASQC
  QPSPDFSHDRQLRLLLSQPIQPMMPGSCDARQPSEVSRTGRQVKYAQSQTVFQNPDAHPA
  NSSSAPMPVLLMGQAVLHPSFPASQPSPLQPAQARQQPPQHYLQVQAPTSLHSEQQDSLL
  LSTYSQQPGTLGYPQPPPAQPQPLRPPRRVSSLSESSGLQQPPR
• Function: Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. The NPAS2-BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. NPAS2 plays an important role in sleep homeostasis and in maintaining circadian behaviors in normal light/dark and feeding conditions and in the effective synchronization of feeding behavior with scheduled food availability. Regulates the gene transcription of key metabolic pathways in the liver and is involved in DNA damage response by regulating several cell cycle and DNA repair genes. Controls the circadian rhythm of NR0B2 expression by binding rhythmically to its promoter. Mediates the diurnal variation in the expression of GABARA1 receptor in the brain and contributes to the regulation of anxiety-like behaviors and GABAergic neurotransmission in the ventral striatum.
• KEGG Pathway: Circadian rhythm (hsa04710)
• Reactome Pathway:
  PPARA activates gene expression (R-HSA-1989781)
  Circadian Clock (R-HSA-400253)
  Heme signaling (R-HSA-9707616)
  BMAL1 (R-HSA-1368108)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Definitive	Biomarker	[1]
Schizoaffective disorder	DISLBW6B	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[4]
Autism	DISV4V1Z	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[7]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[8]
Chronic fatigue syndrome	DIS34WJ5	Strong	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[11]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Genetic Variation	[12]
Depression	DIS3XJ69	Strong	Biomarker	[13]
Drug dependence	DIS9IXRC	Strong	Biomarker	[14]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
Her2-receptor negative breast cancer	DISS605N	Strong	Biomarker	[17]
HER2/NEU overexpressing breast cancer	DISYKID5	Strong	Biomarker	[17]
High blood pressure	DISY2OHH	Strong	Biomarker	[18]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[6]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Biomarker	[10]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[19]
Mental disorder	DIS3J5R8	Strong	Biomarker	[14]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[19]
Neoplasm	DISZKGEW	Strong	Altered Expression	[20]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[8]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[21]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[22]
Parkinson disease	DISQVHKL	Strong	Biomarker	[23]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[24]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[24]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[25]
Vitamin D deficiency	DISAWKYI	Strong	Altered Expression	[26]
Kidney cancer	DISBIPKM	moderate	Biomarker	[27]
Renal carcinoma	DISER9XT	moderate	Biomarker	[27]
Small lymphocytic lymphoma	DIS30POX	moderate	Genetic Variation	[28]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[29]
Anxiety	DISIJDBA	Limited	Biomarker	[30]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[30]
Leiomyosarcoma	DIS6COXM	Limited	Genetic Variation	[31]
Malignant soft tissue neoplasm	DISTC6NO	Limited	Genetic Variation	[31]
Malignant tumor of nasopharynx	DISTGIGF	Limited	Biomarker	[32]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[33]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[32]
Sarcoma	DISZDG3U	Limited	Genetic Variation	[31]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[34]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Neuronal PAS domain-containing protein 2 (NPAS2) affects the response to substance of DTI-015.	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Neuronal PAS domain-containing protein 2 (NPAS2).	[35]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Neuronal PAS domain-containing protein 2 (NPAS2).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Neuronal PAS domain-containing protein 2 (NPAS2).	[42]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Neuronal PAS domain-containing protein 2 (NPAS2).	[38]

8 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 2 (NPAS2).	[36]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuronal PAS domain-containing protein 2 (NPAS2).	[37]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Neuronal PAS domain-containing protein 2 (NPAS2).	[39]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Neuronal PAS domain-containing protein 2 (NPAS2).	[40]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Neuronal PAS domain-containing protein 2 (NPAS2).	[41]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Neuronal PAS domain-containing protein 2 (NPAS2).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Neuronal PAS domain-containing protein 2 (NPAS2).	[44]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID increases the expression of Neuronal PAS domain-containing protein 2 (NPAS2).	[41]

References

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• [19] Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder.Neuropsychopharmacology. 2010 May;35(6):1279-89. doi: 10.1038/npp.2009.230. Epub 2010 Jan 13.
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• [25] Differentially Expressed in Chondrocytes 2 (DEC2) Increases the Expression of IL-1 and Is Abundantly Present in Synovial Membrane in Rheumatoid Arthritis.PLoS One. 2015 Dec 28;10(12):e0145279. doi: 10.1371/journal.pone.0145279. eCollection 2015.
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• [36] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [37] 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.
• [38] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
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