Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZUPU2C)

• DOT Name: Homeobox protein ESX1 (ESX1)
• Synonyms: Extraembryonic, spermatogenesis, homeobox 1
• Gene Name: ESX1
• Related Disease:
  Ependymoma
  Neoplasm
  Tuberculosis
  Advanced cancer
  Azoospermia
  Oligospermia
• UniProt ID: ESX1_HUMAN
• Pfam ID: PF00046
• Sequence:
  MESLRGYTHSDIGYRSLAVGEDIEEVNDEKLTVTSLMARGGEDEENTRSKPEYGTEAENN
  VGTEGSVPSDDQDREGGGGHEPEQQQEEPPLTKPEQQQEEPPLLELKQEQEEPPQTTVEG
  PQPAEGPQTAEGPQPPERKRRRRTAFTQFQLQELENFFDESQYPDVVARERLAARLNLTE
  DRVQVWFQNRRAKWKRNQRVLMLRNTATADLAHPLDMFLGGAYYAAPALDPALCVHLVPQ
  LPRPPVLPVPPMPPRPPMVPMPPRPPIAPMPPMAPVPPGSRMAPVPPGPRMAPVPPWPPM
  APVPPWPPMAPVPTGPPMAPVPPGPPMARVPPGPPMARVPPGPPMAPLPPGPPMAPLPPG
  PPMAPLPPGPPMAPLPPRSHVPHTGLAPVHITWAPVINSYYACPFF
• Function: May coordinately regulate cell cycle progression and transcription during spermatogenesis. Inhibits degradation of polyubiquitinated cyclin A and cyclin B1 and thereby arrests the cell cycle at early M phase. ESXR1-N acts as a transcriptional repressor. Binds to the sequence 5'-TAATGTTATTA-3' which is present within the first intron of the KRAS gene and inhibits its expression. ESXR1-C has the ability to inhibit cyclin turnover.
• Tissue Specificity: Expressed in placenta and testis. Expressed in testicular germ cell tumors.
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ependymoma	DISUMRNZ	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[1]
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Azoospermia	DIS94181	Strong	Altered Expression	[4]
Oligospermia	DIS6YJF3	Strong	Biomarker	[5]

2 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 Homeobox protein ESX1 (ESX1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homeobox protein ESX1 (ESX1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Homeobox protein ESX1 (ESX1).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Homeobox protein ESX1 (ESX1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein ESX1 (ESX1).	[10]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Homeobox protein ESX1 (ESX1).	[11]

References

• [1] Genomic Landscape of Intramedullary Spinal Cord Gliomas.Sci Rep. 2019 Dec 10;9(1):18722. doi: 10.1038/s41598-019-54286-9.
• [2] A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis.J Bacteriol. 2019 Jun 21;201(14):e00760-18. doi: 10.1128/JB.00760-18. Print 2019 Jul 15.
• [3] Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene.Oncogene. 2005 Sep 1;24(38):5878-87. doi: 10.1038/sj.onc.1208736.
• [4] Could analysis of testis-specific genes, as biomarkers in seminal plasma, predict presence of focal spermatogenesis in non-obstructive azoospermia?.Andrologia. 2020 Mar;52(2):e13483. doi: 10.1111/and.13483. Epub 2019 Dec 3.
• [5] ESX1 gene expression as a robust marker of residual spermatogenesis in azoospermic men.Hum Reprod. 2010 Jun;25(6):1398-403. doi: 10.1093/humrep/deq074. Epub 2010 Mar 31.
• [6] 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.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.