Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFH203X)

• DOT Name: Ras-related protein Ral-B (RALB)
• Synonyms: EC 3.6.5.2
• Gene Name: RALB
• Related Disease:
  Acute myelogenous leukaemia
  Pancreatic tumour
  Urinary bladder neoplasm
• UniProt ID: RALB_HUMAN
• PDB ID: 2KE5; 2KWI; 6ZQT; 6ZRN
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MAANKSKGQSSLALHKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGE
  EVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFSITEHESFTATAEFREQILRVKAEEDK
  IPLLVVGNKSDLEERRQVPVEEARSKAEEWGVQYVETSAKTRANVDKVFFDLMREIRTKK
  MSENKDKNGKKSSKNKKSFKERCCLL
• Function: Multifunctional GTPase involved in a variety of cellular processes including gene expression, cell migration, cell proliferation, oncogenic transformation and membrane trafficking. Accomplishes its multiple functions by interacting with distinct downstream effectors. Acts as a GTP sensor for GTP-dependent exocytosis of dense core vesicles. Required both to stabilize the assembly of the exocyst complex and to localize functional exocyst complexes to the leading edge of migrating cells. Required for suppression of apoptosis. In late stages of cytokinesis, upon completion of the bridge formation between dividing cells, mediates exocyst recruitment to the midbody to drive abscission. Involved in ligand-dependent receptor mediated endocytosis of the EGF and insulin receptors.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Phospholipase D sig.ling pathway (hsa04072)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
• Reactome Pathway: p38MAPK events (R-HSA-171007)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Ras-related protein Ral-B (RALB) decreases the response to substance of Cisplatin.	[18]

13 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 Ras-related protein Ral-B (RALB).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras-related protein Ral-B (RALB).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Ral-B (RALB).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein Ral-B (RALB).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Ral-B (RALB).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ras-related protein Ral-B (RALB).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras-related protein Ral-B (RALB).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Ras-related protein Ral-B (RALB).	[11]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Ras-related protein Ral-B (RALB).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ras-related protein Ral-B (RALB).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Ras-related protein Ral-B (RALB).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Ras-related protein Ral-B (RALB).	[16]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Ras-related protein Ral-B (RALB).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ras-related protein Ral-B (RALB).	[13]

References

• [1] Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia.Oncogene. 2017 Jun 8;36(23):3263-3273. doi: 10.1038/onc.2016.471. Epub 2016 Dec 19.
• [2] Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells.Curr Biol. 2006 Dec 19;16(24):2385-94. doi: 10.1016/j.cub.2006.10.023.
• [3] Expression of ral GTPases, their effectors, and activators in human bladder cancer.Clin Cancer Res. 2007 Jul 1;13(13):3803-13. doi: 10.1158/1078-0432.CCR-06-2419.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [13] 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.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [15] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [18] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.