Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLS86J5)

• DOT Name: Ras-related protein Rab-6A (RAB6A)
• Synonyms: Rab-6
• Gene Name: RAB6A
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Cardiomyopathy
  Dengue
  Glioma
  Hepatitis C virus infection
  Immune system disorder
  Immunodeficiency
  Megalencephalic leukoencephalopathy with subcortical cysts
  Neoplasm
  Pheochromocytoma
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Triple negative breast cancer
  Visceral leishmaniasis
  Choroideremia
  Parkinson disease
• UniProt ID: RAB6A_HUMAN
• PDB ID: 1YZQ; 2GIL; 3BBP; 3CWZ; 4DKX; 5LEF
• Pfam ID: PF00071
• Sequence:
  MSTGGDFGNPLRKFKLVFLGEQSVGKTSLITRFMYDSFDNTYQATIGIDFLSKTMYLEDR
  TVRLQLWDTAGQERFRSLIPSYIRDSTVAVVVYDITNVNSFQQTTKWIDDVRTERGSDVI
  IMLVGNKTDLADKRQVSIEEGERKAKELNVMFIETSAKAGYNVKQLFRRVAAALPGMEST
  QDRSREDMIDIKLEKPQEQPVSEGGCSC
• Function: Regulator of COPI-independent retrograde transport from the Golgi apparatus towards the endoplasmic reticulum (ER). Has a low GTPase activity. Recruits VPS13B to the Golgi membrane. Plays a role in neuron projection development (Probable).
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Retrograde transport at the Trans-Golgi-Network (R-HSA-6811440)
  TBC/RABGAPs (R-HSA-8854214)
  RAB geranylgeranylation (R-HSA-8873719)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  Pre-NOTCH Processing in Golgi (R-HSA-1912420)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Cardiomyopathy	DISUPZRG	Strong	Altered Expression	[3]
Dengue	DISKH221	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Genetic Variation	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Immune system disorder	DISAEGPH	Strong	Biomarker	[7]
Immunodeficiency	DIS093I0	Strong	Biomarker	[1]
Megalencephalic leukoencephalopathy with subcortical cysts	DISK9A1M	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[9]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[11]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[12]
Triple negative breast cancer	DISAMG6N	moderate	Altered Expression	[13]
Visceral leishmaniasis	DISTKEYK	moderate	Biomarker	[14]
Choroideremia	DISH4N9B	Limited	Biomarker	[15]
Parkinson disease	DISQVHKL	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras-related protein Rab-6A (RAB6A).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ras-related protein Rab-6A (RAB6A).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Rab-6A (RAB6A).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein Rab-6A (RAB6A).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-6A (RAB6A).	[21]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ras-related protein Rab-6A (RAB6A).	[22]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Ras-related protein Rab-6A (RAB6A).	[23]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Ras-related protein Rab-6A (RAB6A).	[24]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Ras-related protein Rab-6A (RAB6A).	[17]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Ras-related protein Rab-6A (RAB6A).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related protein Rab-6A (RAB6A).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ras-related protein Rab-6A (RAB6A).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Risedronate	DM5FLTY	Approved	Risedronate decreases the prenylation of Ras-related protein Rab-6A (RAB6A).	[25]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Ras-related protein Rab-6A (RAB6A).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ras-related protein Rab-6A (RAB6A).	[28]
NE10790	DMVESO2	Investigative	NE10790 decreases the prenylation of Ras-related protein Rab-6A (RAB6A).	[25]

References

• [1] Rab GTPases implicated in inherited and acquired disorders.Semin Cell Dev Biol. 2011 Feb;22(1):57-68. doi: 10.1016/j.semcdb.2010.12.005. Epub 2010 Dec 13.
• [2] Role of Rab GTPases in Alzheimer's Disease.ACS Chem Neurosci. 2019 Feb 20;10(2):828-838. doi: 10.1021/acschemneuro.8b00387. Epub 2018 Oct 11.
• [3] Increased myocardial Rab GTPase expression: a consequence and cause of cardiomyopathy.Circ Res. 2001 Dec 7;89(12):1130-7. doi: 10.1161/hh2401.100427.
• [4] Rab18 facilitates dengue virus infection by targeting fatty acid synthase to sites of viral replication.J Virol. 2014 Jun;88(12):6793-804. doi: 10.1128/JVI.00045-14. Epub 2014 Apr 2.
• [5] Knockdown of Rab21 inhibits proliferation and induces apoptosis in human glioma cells.Cell Mol Biol Lett. 2017 Dec 19;22:30. doi: 10.1186/s11658-017-0062-0. eCollection 2017.
• [6] Rab5 Enhances Classical Swine Fever Virus Proliferation and Interacts with Viral NS4B Protein to Facilitate Formation of NS4B Related Complex.Front Microbiol. 2017 Aug 8;8:1468. doi: 10.3389/fmicb.2017.01468. eCollection 2017.
• [7] Evidence for defective Rab GTPase-dependent cargo traffic in immune disorders.Exp Cell Res. 2013 Sep 10;319(15):2360-7. doi: 10.1016/j.yexcr.2013.06.012. Epub 2013 Jun 26.
• [8] Recombinant Leishmania Rab6 (rLdRab6) is recognized by sera from visceral leishmaniasis patients.Exp Parasitol. 2016 Nov;170:135-147. doi: 10.1016/j.exppara.2016.09.010. Epub 2016 Sep 22.
• [9] Rab23 promotes the cisplatin resistance of ovarian cancer via the Shh-Gli-ABCG2 signaling pathway.Oncol Lett. 2018 Apr;15(4):5155-5160. doi: 10.3892/ol.2018.7949. Epub 2018 Feb 5.
• [10] The human Rab genes encode a family of GTP-binding proteins related to yeast YPT1 and SEC4 products involved in secretion.J Biol Chem. 1989 Jul 25;264(21):12394-401.
• [11] PRC17, a novel oncogene encoding a Rab GTPase-activating protein, is amplified in prostate cancer.Cancer Res. 2002 Oct 1;62(19):5420-4.
• [12] Predominant Rab-GTPase amplicons contributing to oral squamous cell carcinoma progression to metastasis.Oncotarget. 2015 Sep 8;6(26):21950-63. doi: 10.18632/oncotarget.4277.
• [13] TUFT1 promotes metastasis and chemoresistance in triple negative breast cancer through the TUFT1/Rab5/Rac1 pathway.Cancer Cell Int. 2019 Sep 23;19:242. doi: 10.1186/s12935-019-0961-4. eCollection 2019.
• [14] Leishmania major large RAB GTPase is highly immunogenic in individuals immune to cutaneous and visceral leishmaniasis.Parasit Vectors. 2017 Apr 17;10(1):185. doi: 10.1186/s13071-017-2127-3.
• [15] The Biological Activity of AAV Vectors for Choroideremia Gene Therapy Can Be Measured by InVitro Prenylation of RAB6A.Mol Ther Methods Clin Dev. 2018 Mar 28;9:288-295. doi: 10.1016/j.omtm.2018.03.009. eCollection 2018 Jun 15.
• [16] Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1.EMBO J. 2015 Nov 12;34(22):2840-61. doi: 10.15252/embj.201591593. Epub 2015 Oct 15.
• [17] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] 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.
• [23] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [24] Nicotine modulates the expression of a diverse set of genes in the neuronal SH-SY5Y cell line. J Biol Chem. 2003 May 2;278(18):15633-40.
• [25] Selective inhibition of Rab prenylation by a phosphonocarboxylate analogue of risedronate induces apoptosis, but not S-phase arrest, in human myeloma cells. Int J Cancer. 2006 Sep 15;119(6):1254-61. doi: 10.1002/ijc.21977.
• [26] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [27] 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.
• [28] 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.
• [29] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [30] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.