Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGLY3I7)

• DOT Name: Rab GDP dissociation inhibitor beta (GDI2)
• Synonyms: Rab GDI beta; Guanosine diphosphate dissociation inhibitor 2; GDI-2
• Gene Name: GDI2
• Related Disease:
  Esophageal squamous cell carcinoma
  Advanced cancer
  Carcinoma
  Lung cancer
  Lung carcinoma
  Medulloblastoma
  Neoplasm
  Non-small-cell lung cancer
  Intellectual disability
  Rett syndrome
• UniProt ID: GDIB_HUMAN
• Pfam ID: PF00996
• Sequence:
  MNEEYDVIVLGTGLTECILSGIMSVNGKKVLHMDRNPYYGGESASITPLEDLYKRFKIPG
  SPPESMGRGRDWNVDLIPKFLMANGQLVKMLLYTEVTRYLDFKVTEGSFVYKGGKIYKVP
  STEAEALASSLMGLFEKRRFRKFLVYVANFDEKDPRTFEGIDPKKTTMRDVYKKFDLGQD
  VIDFTGHALALYRTDDYLDQPCYETINRIKLYSESLARYGKSPYLYPLYGLGELPQGFAR
  LSAIYGGTYMLNKPIEEIIVQNGKVIGVKSEGEIARCKQLICDPSYVKDRVEKVGQVIRV
  ICILSHPIKNTNDANSCQIIIPQNQVNRKSDIYVCMISFAHNVAAQGKYIAIVSTTVETK
  EPEKEIRPALELLEPIEQKFVSISDLLVPKDLGTESQIFISRTYDATTHFETTCDDIKNI
  YKRMTGSEFDFEEMKRKKNDIYGED
• Function: GDP-dissociation inhibitor preventing the GDP to GTP exchange of most Rab proteins. By keeping these small GTPases in their inactive GDP-bound form regulates intracellular membrane trafficking. Negatively regulates protein transport to the cilium and ciliogenesis through the inhibition of RAB8A.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[5]
Rett syndrome	DISGG5UV	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Rab GDP dissociation inhibitor beta (GDI2).	[15]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[16]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Rab GDP dissociation inhibitor beta (GDI2).	[22]

3 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 Rab GDP dissociation inhibitor beta (GDI2).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Rab GDP dissociation inhibitor beta (GDI2).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Rab GDP dissociation inhibitor beta (GDI2).	[20]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Rab GDP dissociation inhibitor beta (GDI2).	[18]

References

• [1] Using proteomic approach to identify tumor-associated proteins as biomarkers in human esophageal squamous cell carcinoma.J Proteome Res. 2011 Jun 3;10(6):2863-72. doi: 10.1021/pr200141c. Epub 2011 May 3.
• [2] Monitoring the response of urothelial precancerous lesions to Bacillus Calmette-Guerin at the proteome level in an in vivo rat model.Cancer Immunol Immunother. 2018 Jan;67(1):67-77. doi: 10.1007/s00262-017-2063-2. Epub 2017 Sep 15.
• [3] Genetic drivers of metastatic dissemination in sonic hedgehog medulloblastoma.Acta Neuropathol Commun. 2014 Jul 25;2:85. doi: 10.1186/s40478-014-0085-y.
• [4] Bioinformatics analysis of Rab GDP dissociation inhibitor beta and its expression in non-small cell lung cancer.Diagn Pathol. 2014 Nov 4;9:201. doi: 10.1186/s13000-014-0201-0.
• [5] Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor.Hum Mol Genet. 1998 Aug;7(8):1311-5. doi: 10.1093/hmg/7.8.1311.
• [6] Evaluation of two X chromosomal candidate genes for Rett syndrome: glutamate dehydrogenase-2 (GLUD2) and rab GDP-dissociation inhibitor (GDI1).Am J Med Genet. 1998 Jun 30;78(2):169-72.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] 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.
• [14] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [17] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [18] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [19] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.