Details of Drug Off-Target (DOT)

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

• DOT Name: Basic helix-loop-helix ARNT-like protein 2 (BMAL2)
• Synonyms: Aryl hydrocarbon receptor nuclear translocator-like protein 2; Basic-helix-loop-helix-PAS protein MOP9; Brain and muscle ARNT-like 2; CYCLE-like factor; CLIF; Class E basic helix-loop-helix protein 6; bHLHe6; Member of PAS protein 9; PAS domain-containing protein 9
• Gene Name: BMAL2
• UniProt ID: BMAL2_HUMAN
• PDB ID: 2KDK
• Pfam ID: PF00010 ; PF00989 ; PF14598
• Sequence:
  MAAEEEAAAGGKVLREENQCIAPVVSSRVSPGTRPTAMGSFSSHMTEFPRKRKGSDSDPS
  QSGIMTEKVVEKLSQNPLTYLLSTRIEISASSGSRVEDGEHQVKMKAFREAHSQTEKRRR
  DKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLRSLKGLTNSYVGSNYRPSFLQDN
  ELRHLILKTAEGFLFVVGCERGKILFVSKSVSKILNYDQASLTGQSLFDFLHPKDVAKVK
  EQLSSFDISPREKLIDAKTGLQVHSNLHAGRTRVYSGSRRSFFCRIKSCKISVKEEHGCL
  PNSKKKEHRKFYTIHCTGYLRSWPPNIVGMEEERNSKKDNSNFTCLVAIGRLQPYIVPQN
  SGEINVKPTEFITRFAVNGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHNNLTDKH
  KAVLQSKEKILTDSYKFRAKDGSFVTLKSQWFSFTNPWTKELEYIVSVNTLVLGHSEPGE
  ASFLPCSSQSSEESSRQSCMSVPGMSTGTVLGAGSIGTDIANEILDLQRLQSSSYLDDSS
  PTGLMKDTHTVNCRSMSNKELFPPSPSEMGELEATRQNQSTVAVHSHEPLLSDGAQLDFD
  ALCDNDDTAMAAFMNYLEAEGGLGDPGDFSDIQWTL
• 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 CLOCK-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1.
• Tissue Specificity: Expressed in fetal brain. Highly expressed in brain and placenta. Lower levels in heart, liver, thymus, kidney and lung. Located to endothelial cells and neuronal cells of the suprachiasmatic nucleus (SCN). Also detected in endothelial cells of the heart, lung and kidney. In the brain, specifically expressed in the thalamus, hippocampus and amygdala.
• Reactome Pathway: BMAL1 (R-HSA-1368108)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[7]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[2]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Basic helix-loop-helix ARNT-like protein 2 (BMAL2).	[13]

References

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• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] 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.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] 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.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [9] 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.
• [10] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.