Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDZT6LP)

• DOT Name: Ras-related protein Rab-7L1 (RAB29)
• Synonyms: Rab-7-like protein 1; Ras-related protein Rab-29
• Gene Name: RAB29
• Related Disease:
  Alzheimer disease
  Hepatitis C virus infection
  Mycobacterium infection
  Amyotrophic lateral sclerosis
  Frontotemporal dementia
  Neuroblastoma
  Pick disease
• UniProt ID: RAB7L_HUMAN
• PDB ID: 6HH2
• Pfam ID: PF00071
• Sequence:
  MGSRDHLFKVLVVGDAAVGKTSLVQRYSQDSFSKHYKSTVGVDFALKVLQWSDYEIVRLQ
  LWDIAGQERFTSMTRLYYRDASACVIMFDVTNATTFSNSQRWKQDLDSKLTLPNGEPVPC
  LLLANKCDLSPWAVSRDQIDRFSKENGFTGWTETSVKENKNINEAMRVLIEKMMRNSTED
  IMSLSTQGDYINLQTKSSSWSCC
• Function: The small GTPases Rab are key regulators in vesicle trafficking. Essential for maintaining the integrity of the endosome-trans-Golgi network structure. Together with LRRK2, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose 6 phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner. Recruits LRRK2 to the Golgi complex and stimulates LRRK2 kinase activity. Regulates neuronal process morphology in the intact central nervous system (CNS). May play a role in the formation of typhoid toxin transport intermediates during Salmonella enterica serovar Typhi (S.Typhi) epithelial cell infection.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: RAB geranylgeranylation (R-HSA-8873719)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[2]
Mycobacterium infection	DISNSMUD	Strong	Biomarker	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[4]
Frontotemporal dementia	DISKYHXL	Limited	Biomarker	[4]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[4]
Pick disease	DISP6X50	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Ras-related protein Rab-7L1 (RAB29) affects the response to substance of Topotecan.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ras-related protein Rab-7L1 (RAB29).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ras-related protein Rab-7L1 (RAB29).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras-related protein Rab-7L1 (RAB29).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ras-related protein Rab-7L1 (RAB29).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Rab-7L1 (RAB29).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras-related protein Rab-7L1 (RAB29).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ras-related protein Rab-7L1 (RAB29).	[11]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Ras-related protein Rab-7L1 (RAB29).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ras-related protein Rab-7L1 (RAB29).	[13]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Ras-related protein Rab-7L1 (RAB29).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ras-related protein Rab-7L1 (RAB29).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ras-related protein Rab-7L1 (RAB29).	[16]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Ras-related protein Rab-7L1 (RAB29).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ras-related protein Rab-7L1 (RAB29).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-related protein Rab-7L1 (RAB29).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related protein Rab-7L1 (RAB29).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ras-related protein Rab-7L1 (RAB29).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ras-related protein Rab-7L1 (RAB29).	[21]

References

• [1] Association of Parkinson's Disease GWAS-Linked Loci with Alzheimer's Disease in Han Chinese.Mol Neurobiol. 2017 Jan;54(1):308-318. doi: 10.1007/s12035-015-9649-5. Epub 2016 Jan 6.
• [2] Roles for endocytic trafficking and phosphatidylinositol 4-kinase III alpha in hepatitis C virus replication.Proc Natl Acad Sci U S A. 2009 May 5;106(18):7577-82. doi: 10.1073/pnas.0902693106. Epub 2009 Apr 17.
• [3] Mycobacterial PknG Targets the Rab7l1 Signaling Pathway To Inhibit Phagosome-Lysosome Fusion.J Immunol. 2018 Sep 1;201(5):1421-1433. doi: 10.4049/jimmunol.1800530. Epub 2018 Jul 23.
• [4] C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia.Brain. 2017 Apr 1;140(4):887-897. doi: 10.1093/brain/awx024.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] 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.
• [8] 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.
• [9] 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.
• [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] 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.
• [12] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.