Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBQIF0H)

• DOT Name: Protein BEX1 (BEX1)
• Synonyms: Brain-expressed X-linked protein 1
• Gene Name: BEX1
• Related Disease:
  Ependymoma
  Acute myelogenous leukaemia
  B-cell neoplasm
  Cardiac disease
  Cardiac failure
  Cardiomyopathy
  Congestive heart failure
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Leukemia
  Lung adenocarcinoma
  Malignant glioma
  Neoplasm
  Squamous cell carcinoma
• UniProt ID: BEX1_HUMAN
• Pfam ID: PF04538
• Sequence:
  MESKEKRAVNSLSMENANQENEEKEQVANKGEPLALPLDAGEYCVPRGNRRRFRVRQPIL
  QYRWDMMHRLGEPQARMREENMERIGEEVRQLMEKLREKQLSHSLRAVSTDPPHHDHHDE
  FCLMP
• Function: Signaling adapter molecule involved in p75NTR/NGFR signaling. Plays a role in cell cycle progression and neuronal differentiation. Inhibits neuronal differentiation in response to nerve growth factor (NGF). May act as a link between the cell cycle and neurotrophic factor signaling, possibly by functioning as an upstream modulator of receptor signaling, coordinating biological responses to external signals with internal cellular states. In absence of reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B) complex: associates with FEM1B via zinc, thereby preventing association between FEM1B and its substrates.
• Tissue Specificity: Expressed in central nervous system, with high level in pituitary, cerebellum and temporal lobe. Expressed in lung, skeletal muscle, peripheral blood leukocyte, stomach, lymph node, trachea and bone marrow. Highly expressed in acute myeloid leukemia.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ependymoma	DISUMRNZ	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Cardiac disease	DISVO1I5	Strong	Biomarker	[4]
Cardiac failure	DISDC067	Strong	Altered Expression	[4]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Leukemia	DISNAKFL	Strong	Altered Expression	[7]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[8]
Malignant glioma	DISFXKOV	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[10]

13 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 Protein BEX1 (BEX1).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein BEX1 (BEX1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein BEX1 (BEX1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein BEX1 (BEX1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein BEX1 (BEX1).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein BEX1 (BEX1).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein BEX1 (BEX1).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein BEX1 (BEX1).	[19]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Protein BEX1 (BEX1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein BEX1 (BEX1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein BEX1 (BEX1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein BEX1 (BEX1).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Protein BEX1 (BEX1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein BEX1 (BEX1).	[16]

References

• [1] Epigenetic genome-wide analysis identifies BEX1 as a candidate tumour suppressor gene in paediatric intracranial ependymoma.Cancer Lett. 2014 Apr 28;346(1):34-44. doi: 10.1016/j.canlet.2013.12.005. Epub 2013 Dec 11.
• [2] BEX1 acts as a tumor suppressor in acute myeloid leukemia.Oncotarget. 2015 Aug 28;6(25):21395-405. doi: 10.18632/oncotarget.4095.
• [3] Bex1 attenuates neuronal apoptosis in rat intracerebral hemorrhage model.Pathol Res Pract. 2018 Apr;214(4):527-535. doi: 10.1016/j.prp.2018.02.012. Epub 2018 Feb 21.
• [4] BEX1 is an RNA-dependent mediator of cardiomyopathy.Nat Commun. 2017 Nov 30;8(1):1875. doi: 10.1038/s41467-017-02005-1.
• [5] Low expression of BEX1 predicts poor prognosis in patients with esophageal squamous cell cancer.Oncol Rep. 2018 Nov;40(5):2778-2787. doi: 10.3892/or.2018.6647. Epub 2018 Aug 17.
• [6] An X-chromosomal association study identifies a susceptibility locus at Xq22.1 for hepatitis B virus-related hepatocellular carcinoma.Clin Res Hepatol Gastroenterol. 2013 Dec;37(6):586-95. doi: 10.1016/j.clinre.2013.09.002. Epub 2013 Oct 25.
• [7] Inhibition of apoptosis by downregulation of hBex1, a novel mechanism, contributes to the chemoresistance of Bcr/Abl+ leukemic cells.Carcinogenesis. 2009 Jan;30(1):35-42. doi: 10.1093/carcin/bgn251. Epub 2008 Nov 21.
• [8] Diagnostic and prognostic value of the BEX family in lung adenocarcinoma.Oncol Lett. 2019 Nov;18(5):5523-5533. doi: 10.3892/ol.2019.10905. Epub 2019 Sep 20.
• [9] Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma.Cancer Res. 2006 Jul 1;66(13):6665-74. doi: 10.1158/0008-5472.CAN-05-4453.
• [10] Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma.J Pathol. 2013 Jul;230(3):298-309. doi: 10.1002/path.4173. Epub 2013 Mar 21.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] 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.
• [18] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [19] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [20] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [21] Chlorophyllin significantly reduces benzo[a]pyrene-DNA adduct formation and alters cytochrome P450 1A1 and 1B1 expression and EROD activity in normal human mammary epithelial cells. Environ Mol Mutagen. 2009 Mar;50(2):134-44.
• [22] 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.
• [23] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.