Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG36NI7)

• DOT Name: Ral guanine nucleotide dissociation stimulator (RALGDS)
• Synonyms: RalGDS; Ral guanine nucleotide exchange factor; RalGEF
• Gene Name: RALGDS
• Related Disease:
  Advanced cancer
  Brain cancer
  Brain neoplasm
  Intellectual disability
  Medulloblastoma
  Melanoma
  Prostate cancer
  Prostate carcinoma
  Skin neoplasm
  Squamous cell carcinoma
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
  Amyotrophic lateral sclerosis type 4
  Complex neurodevelopmental disorder
  Enterovirus infection
  Neoplasm
• UniProt ID: GNDS_HUMAN
• PDB ID: 1RAX; 2B3A; 2RGF; 3KH0
• Pfam ID: PF00788 ; PF00617 ; PF00618
• Sequence:
  MVQRMWAEAAGPAGGAEPLFPGSRRSRSVWDAVRLEVGVPDSCPVVLHSFTQLDPDLPRP
  ESSTQEIGEELINGVIYSISLRKVQLHHGGNKGQRWLGYENESALNLYETCKVRTVKAGT
  LEKLVEHLVPAFQGSDLSYVTIFLCTYRAFTTTQQVLDLLFKRYGRCDALTASSRYGCIL
  PYSDEDGGPQDQLKNAISSILGTWLDQYSEDFCQPPDFPCLKQLVAYVQLNMPGSDLERR
  AHLLLAQLEHSEPIEAEPEALSPVPALKPTPELELALTPARAPSPVPAPAPEPEPAPTPA
  PGSELEVAPAPAPELQQAPEPAVGLESAPAPALELEPAPEQDPAPSQTLELEPAPAPVPS
  LQPSWPSPVVAENGLSEEKPHLLVFPPDLVAEQFTLMDAELFKKVVPYHCLGSIWSQRDK
  KGKEHLAPTIRATVTQFNSVANCVITTCLGNRSTKAPDRARVVEHWIEVARECRILKNFS
  SLYAILSALQSNSIHRLKKTWEDVSRDSFRIFQKLSEIFSDENNYSLSRELLIKEGTSKF
  ATLEMNPKRAQKRPKETGIIQGTVPYLGTFLTDLVMLDTAMKDYLYGRLINFEKRRKEFE
  VIAQIKLLQSACNNYSIAPDEQFGAWFRAVERLSETESYNLSCELEPPSESASNTLRTKK
  NTAIVKRWSDRQAPSTELSTSGSSHSKSCDQLRCGPYLSSGDIADALSVHSAGSSSSDVE
  EINISFVPESPDGQEKKFWESASQSSPETSGISSASSSTSSSSASTTPVAATRTHKRSVS
  GLCNSSSALPLYNQQVGDCCIIRVSLDVDNGNMYKSILVTSQDKAPAVIRKAMDKHNLEE
  EEPEDYELLQILSDDRKLKIPENANVFYAMNSTANYDFVLKKRTFTKGVKVKHGASSTLP
  RMKQKGLKIAKGIF
• Function: Functions as a guanine nucleotide exchange factor (GEF) activating either RalA or RalB GTPases and plays an important role in intracellular transport. Interacts and acts as an effector molecule for R-Ras, H-Ras, K-Ras, and Rap. During bacterial clearance, recognizes 'Lys-33'-linked polyubiquitinated TRAF3 and subsequently mediates assembly of the exocyst complex.
• 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)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  RAF/MAP kinase cascade (R-HSA-5673001)
  p38MAPK events (R-HSA-171007)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Brain cancer	DISBKFB7	Strong	Genetic Variation	[2]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[2]
Intellectual disability	DISMBNXP	Strong	Biomarker	[3]
Medulloblastoma	DISZD2ZL	Strong	Genetic Variation	[2]
Melanoma	DIS1RRCY	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Skin neoplasm	DIS16DDV	Strong	Biomarker	[6]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[7]
Matthew-Wood syndrome	DISA7HR7	moderate	Genetic Variation	[8]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Altered Expression	[8]
Amyotrophic lateral sclerosis type 4	DISSDHYG	Limited	Biomarker	[9]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal recessive	[10]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[17]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[20]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[23]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[24]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Ral guanine nucleotide dissociation stimulator (RALGDS).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Ral guanine nucleotide dissociation stimulator (RALGDS).	[14]

References

• [1] Tumour prevention by a single antibody domain targeting the interaction of signal transduction proteins with RAS.EMBO J. 2007 Jul 11;26(13):3250-9. doi: 10.1038/sj.emboj.7601744. Epub 2007 Jun 14.
• [2] Implementation of a High-Throughput Pilot Screen in Peptide Hydrogel-Based Three-Dimensional Cell Cultures.SLAS Discov. 2019 Aug;24(7):714-723. doi: 10.1177/2472555219844570. Epub 2019 Apr 30.
• [3] Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
• [4] No evidence of RALGDS mutations in cutaneous melanoma.Melanoma Res. 2007 Dec;17(6):410-2. doi: 10.1097/CMR.0b013e3282ef4178.
• [5] MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway.J Exp Clin Cancer Res. 2019 Sep 5;38(1):391. doi: 10.1186/s13046-019-1374-x.
• [6] RalGDS is required for tumor formation in a model of skin carcinogenesis.Cancer Cell. 2005 Mar;7(3):219-26. doi: 10.1016/j.ccr.2005.01.029.
• [7] The human Rgr oncogene is overexpressed in T-cell malignancies and induces transformation by acting as a GEF for Ras and Ral.Oncogene. 2011 Aug 25;30(34):3661-71. doi: 10.1038/onc.2011.93. Epub 2011 Mar 28.
• [8] Response to MLN8237 in pancreatic cancer is not dependent on RalA phosphorylation.Mol Cancer Ther. 2014 Jan;13(1):122-33. doi: 10.1158/1535-7163.MCT-12-1232. Epub 2013 Nov 12.
• [9] A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34.Neurogenetics. 2000 Sep;3(1):1-6. doi: 10.1007/pl00022976.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] Fibronectin Facilitates Enterovirus 71 Infection by Mediating Viral Entry.J Virol. 2018 Apr 13;92(9):e02251-17. doi: 10.1128/JVI.02251-17. Print 2018 May 1.
• [12] Multifunctional Peptide-Amphiphile End-Capped Mesoporous Silica Nanoparticles for Tumor Targeting Drug Delivery.ACS Appl Mater Interfaces. 2017 Jan 25;9(3):2093-2103. doi: 10.1021/acsami.6b12647. Epub 2017 Jan 12.
• [13] 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.
• [14] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [25] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.