Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ3X84T)

• DOT Name: Elongin-B (ELOB)
• Synonyms: EloB; Elongin 18 kDa subunit; RNA polymerase II transcription factor SIII subunit B; SIII p18; Transcription elongation factor B polypeptide 2
• Gene Name: ELOB
• Related Disease:
  Asthma
  Breast carcinoma
  Brugada syndrome
  Clear cell renal carcinoma
  Epithelial ovarian cancer
  Hemangioblastoma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pheochromocytoma
  Polycythemia
  Ventricular tachycardia
  Von hippel-lindau disease
  Cutaneous mastocytosis
• UniProt ID: ELOB_HUMAN
• PDB ID: 1LM8 ; 1LQB ; 1VCB ; 2C9W ; 2IZV ; 2JZ3 ; 2MA9 ; 3DCG ; 3ZKJ ; 3ZNG ; 3ZRC ; 3ZRF ; 3ZTC ; 3ZTD ; 3ZUN ; 4AJY ; 4AWJ ; 4B95 ; 4B9K ; 4BKS ; 4BKT ; 4N9F ; 4W9C ; 4W9D ; 4W9E ; 4W9F ; 4W9G ; 4W9H ; 4W9I ; 4W9J ; 4W9K ; 4W9L ; 4WQO ; 5BO4 ; 5LLI ; 5N4W ; 5NVV ; 5NVW ; 5NVX ; 5NVY ; 5NVZ ; 5NW0 ; 5NW1 ; 5NW2 ; 5T35 ; 6BVB ; 6C5X ; 6FMI ; 6FMJ ; 6FMK ; 6GFX ; 6GFY ; 6GFZ ; 6GMN ; 6GMQ ; 6GMR ; 6GMX ; 6HAX ; 6HAY ; 6HR2 ; 6I4X ; 6I5J ; 6I5N ; 6I7Q ; 6I7R ; 6P59 ; 6R6H ; 6R7F ; 6R7H ; 6R7I ; 6R7N ; 6SIS ; 6V9H ; 6ZHC ; 7CJB ; 7JTO ; 7JTP ; 7KHH ; 7M6T ; 7PI4 ; 7PLO ; 7Q2J ; 7S4E ; 7UPN ; 7Z6L ; 7Z76 ; 7Z77 ; 7ZLM ; 7ZLN ; 7ZLO ; 7ZLP ; 7ZLR ; 7ZLS ; 7ZNT ; 8BB2 ; 8BB3 ; 8BB4 ; 8BB5 ; 8BDI ; 8BDJ ; 8BDL ; 8BDM ; 8BDN ; 8BDO ; 8BDS ; 8BDT ; 8BDX ; 8BEB ; 8C13 ; 8CQE ; 8CQK ; 8CQL ; 8CX0 ; 8CX1 ; 8CX2 ; 8EBN ; 8EI3 ; 8EWV ; 8FVI ; 8FVJ ; 8G1P ; 8G1Q ; 8JAL ; 8JAQ ; 8JAR ; 8JAS ; 8JAU ; 8JAV ; 8OEV ; 8OEW ; 8OF0 ; 8P0F ; 8PC2 ; 8QU8 ; 8QVU ; 8QW6 ; 8QW7
• Pfam ID: PF00240
• Sequence:
  MDVFLMIRRHKTTIFTDAKESSTVFELKRIVEGILKRPPDEQRLYKDDQLLDDGKTLGEC
  GFTSQTARPQAPATVGLAFRADDTFEALCIEPFSSPPELPDVMKPQDSGSSANEQAVQ
• Function: SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex). In embryonic stem cells, the elongin BC complex is recruited by EPOP to Polycomb group (PcG) target genes in order generate genomic region that display both active and repressive chromatin properties, an important feature of pluripotent stem cells; Core component of multiple cullin-RING-based ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins. This includes the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes. As part of a multisubunit ubiquitin ligase complex composed of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5; polyubiquitinates monoubiquitinated POLR2A. A number of ECS complexes (containing either KLHDC2, KLHDC3, KLHDC10, APPBP2, FEM1A, FEM1B or FEM1C as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. ECS(LRR1) ubiquitinates MCM7 and promotes CMG replisome disassembly by VCP and chromatin extraction during S-phase.
• KEGG Pathway:
  HIF-1 sig.ling pathway (hsa04066)
  Ubiquitin mediated proteolysis (hsa04120)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  Vif-mediated degradation of APOBEC3G (R-HSA-180585)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Neddylation (R-HSA-8951664)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Inactivation of CSF3 (G-CSF) signaling (R-HSA-9705462)
  Antigen processing (R-HSA-983168)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Brugada syndrome	DISSGN0E	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Hemangioblastoma	DIS1EAZC	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[5]
Pheochromocytoma	DIS56IFV	Strong	Genetic Variation	[6]
Polycythemia	DIS8B6VW	Strong	Biomarker	[4]
Ventricular tachycardia	DISIBXJ3	Strong	Biomarker	[3]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Biomarker	[4]
Cutaneous mastocytosis	DISLBZEF	Limited	Biomarker	[7]

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 Elongin-B (ELOB).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Elongin-B (ELOB).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Elongin-B (ELOB).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Elongin-B (ELOB).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Elongin-B (ELOB).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Elongin-B (ELOB).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Elongin-B (ELOB).	[13]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Elongin-B (ELOB).	[10]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Elongin-B (ELOB).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Elongin-B (ELOB).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Elongin-B (ELOB).	[16]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Elongin-B (ELOB).	[17]

References

• [1] Change in capnogram waveform is associated with bronchodilator response and asthma control in children.Pediatr Pulmonol. 2019 Jun;54(6):698-705. doi: 10.1002/ppul.24282. Epub 2019 Feb 26.
• [2] No evidence for DNA methylation of von Hippel-Lindau ubiquitin ligase complex genes in breast cancer.Breast Cancer Res Treat. 2010 Dec;124(3):853-6. doi: 10.1007/s10549-010-1087-5. Epub 2010 Aug 3.
• [3] Prediction of ventricular tachyarrhythmia in Brugada syndrome by right ventricular outflow tract conduction delay signs.J Cardiovasc Electrophysiol. 2018 Jul;29(7):998-1003. doi: 10.1111/jce.13496. Epub 2018 Apr 20.
• [4] An integrated computational approach can classify VHL missense mutations according to risk of clear cell renal carcinoma.Hum Mol Genet. 2014 Nov 15;23(22):5976-88. doi: 10.1093/hmg/ddu321. Epub 2014 Jun 26.
• [5] TCEB2 confers resistance to VEGF-targeted therapy in ovarian cancer.Oncol Rep. 2016 Jan;35(1):359-65. doi: 10.3892/or.2015.4388. Epub 2015 Nov 3.
• [6] Expression of the von Hippel-Lindau-binding protein-1 (Vbp1) in fetal and adult mouse tissues.Hum Mol Genet. 1999 Feb;8(2):229-36. doi: 10.1093/hmg/8.2.229.
• [7] Radiofrequency ablation versus laparoscopic hepatectomy for hepatocellular carcinoma: A real world single center study.Eur J Surg Oncol. 2020 Apr;46(4 Pt A):548-559. doi: 10.1016/j.ejso.2019.10.026. Epub 2019 Oct 24.
• [8] 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.
• [9] 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.
• [10] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.