Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQE5QQ2)

• DOT Name: Ras-related protein Rab-5C (RAB5C)
• Synonyms: EC 3.6.5.2; L1880; RAB5L
• Gene Name: RAB5C
• Related Disease:
  Advanced cancer
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  B-cell acute lymphoblastic leukaemia
  Hypothyroidism
  STAT3-related early-onset multisystem autoimmune disease
  Vitiligo
  Rectal adenocarcinoma
  Rectal carcinoma
• UniProt ID: RAB5C_HUMAN
• PDB ID: 4KYI
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MAGRGGAARPNGPAAGNKICQFKLVLLGESAVGKSSLVLRFVKGQFHEYQESTIGAAFLT
  QTVCLDDTTVKFEIWDTAGQERYHSLAPMYYRGAQAAIVVYDITNTDTFARAKNWVKELQ
  RQASPNIVIALAGNKADLASKRAVEFQEAQAYADDNSLLFMETSAKTAMNVNEIFMAIAK
  KLPKNEPQNATGAPGRNRGVDLQENNPASRSQCCSN
• Function: Protein transport. Probably involved in vesicular traffic.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Mitophagy - animal (hsa04137)
  Endocytosis (hsa04144)
  Phagosome (hsa04145)
  Efferocytosis (hsa04148)
  Vasopressin-regulated water reabsorption (hsa04962)
  Salmonella infection (hsa05132)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  TBC/RABGAPs (R-HSA-8854214)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  RAB geranylgeranylation (R-HSA-8873719)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[2]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[2]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Biomarker	[3]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[2]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[2]
Vitiligo	DISR05SL	Strong	Genetic Variation	[4]
Rectal adenocarcinoma	DIS8R9VO	Limited	Biomarker	[5]
Rectal carcinoma	DIS8FRR7	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ras-related protein Rab-5C (RAB5C).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras-related protein Rab-5C (RAB5C).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein Rab-5C (RAB5C).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-5C (RAB5C).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Ras-related protein Rab-5C (RAB5C).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Ras-related protein Rab-5C (RAB5C).	[11]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Ras-related protein Rab-5C (RAB5C).	[7]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Ras-related protein Rab-5C (RAB5C).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Ras-related protein Rab-5C (RAB5C).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Ras-related protein Rab-5C (RAB5C).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related protein Rab-5C (RAB5C).	[15]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Ras-related protein Rab-5C (RAB5C).	[16]

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 Rab-5C (RAB5C).	[13]

References

• [1] Rab5c promotes AMAP1-PRKD2 complex formation to enhance 1 integrin recycling in EGF-induced cancer invasion.J Cell Biol. 2012 Jun 25;197(7):983-96. doi: 10.1083/jcb.201201065.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Regulation of RAB5C is important for the growth inhibitory effects of MiR-509 in human precursor-B acute lymphoblastic leukemia.PLoS One. 2014 Nov 4;9(11):e111777. doi: 10.1371/journal.pone.0111777. eCollection 2014.
• [4] Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.Nat Genet. 2016 Nov;48(11):1418-1424. doi: 10.1038/ng.3680. Epub 2016 Oct 10.
• [5] Rab5C enhances resistance to ionizing radiation in rectal cancer.J Mol Med (Berl). 2019 Jun;97(6):855-869. doi: 10.1007/s00109-019-01760-6. Epub 2019 Apr 9.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [11] 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.
• [12] 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.
• [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] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [15] 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.
• [16] 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.