Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9CKHDC)

• DOT Name: Rho GTPase-activating protein 15 (ARHGAP15)
• Synonyms: ArhGAP15; Rho-type GTPase-activating protein 15
• Gene Name: ARHGAP15
• Related Disease:
  Breast carcinoma
  Diverticulitis
  Glioma
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Mood disorder
  Non-insulin dependent diabetes
  Schizophrenia
  Tooth agenesis
  Tooth agenesis, selective, 1
  Coronary heart disease
  Neoplasm
  Advanced cancer
  Colorectal carcinoma
  Pancreatic ductal carcinoma
• UniProt ID: RHG15_HUMAN
• PDB ID: 3BYI
• Pfam ID: PF00169 ; PF00620
• Sequence:
  MQKSTNSDTSVETLNSTRQGTGAVQMRIKNANSHHDRLSQSKSMILTDVGKVTEPISRHR
  RNHSQHILKDVIPPLEQLMVEKEGYLQKAKIADGGKKLRKNWSTSWIVLSSRRIEFYKES
  KQQALSNMKTGHKPESVDLCGAHIEWAKEKSSRKNVFQITTVSGNEFLLQSDIDFIILDW
  FHAIKNAIDRLPKDSSCPSRNLELFKIQRSSSTELLSHYDSDIKEQKPEHRKSLMFRLHH
  SASDTSDKNRVKSRLKKFITRRPSLKTLQEKGLIKDQIFGSHLHKVCERENSTVPWFVKQ
  CIEAVEKRGLDVDGIYRVSGNLATIQKLRFIVNQEEKLNLDDSQWEDIHVVTGALKMFFR
  ELPEPLFPYSFFEQFVEAIKKQDNNTRIEAVKSLVQKLPPPNRDTMKVLFGHLTKIVAKA
  SKNLMSTQSLGIVFGPTLLRAENETGNMAIHMVYQNQIAELMLSEYSKIFGSEED
• Function: GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Has activity toward RAC1. Overexpression results in an increase in actin stress fibers and cell contraction.
• Tissue Specificity: Expressed in lung, liver and lymphoid cells.
• Reactome Pathway:
  RAC3 GTPase cycle (R-HSA-9013423)
  RAC1 GTPase cycle (R-HSA-9013149)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Diverticulitis	DIS1AK7Q	Strong	Genetic Variation	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[5]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[6]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[7]
Tooth agenesis	DIS1PWC7	Strong	Genetic Variation	[8]
Tooth agenesis, selective, 1	DIS84ERL	Strong	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[9]
Neoplasm	DISZKGEW	Disputed	Biomarker	[1]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[3]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[3]

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 Rho GTPase-activating protein 15 (ARHGAP15).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[18]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rho GTPase-activating protein 15 (ARHGAP15).	[15]

References

• [1] ARHGAP15 in Human Breast Carcinoma: A Potent Tumor Suppressor Regulated by Androgens.Int J Mol Sci. 2018 Mar 10;19(3):804. doi: 10.3390/ijms19030804.
• [2] Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis.Nat Commun. 2017 Jun 6;8:15789. doi: 10.1038/ncomms15789.
• [3] Decreased expression of ARHGAP15 promotes the development of colorectal cancer through PTEN/AKT/FOXO1 axis.Cell Death Dis. 2018 Jun 4;9(6):673. doi: 10.1038/s41419-018-0707-6.
• [4] ARHGAP15 regulates lung cancer cell proliferation and metastasis via the STAT3 pathway.Eur Rev Med Pharmacol Sci. 2019 Jul;23(13):5840-5850. doi: 10.26355/eurrev_201907_18326.
• [5] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [6] Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.Science. 2007 Jun 1;316(5829):1331-6. doi: 10.1126/science.1142358. Epub 2007 Apr 26.
• [7] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [8] Rare and Common Variants Conferring Risk of Tooth Agenesis.J Dent Res. 2018 May;97(5):515-522. doi: 10.1177/0022034517750109. Epub 2018 Jan 24.
• [9] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [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] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [17] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [18] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [19] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [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.