Details of Drug Off-Target (DOT)

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

• DOT Name: Rho GTPase-activating protein 5 (ARHGAP5)
• Synonyms: Rho-type GTPase-activating protein 5; p190-B
• Gene Name: ARHGAP5
• Related Disease:
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Non-small-cell lung cancer
  Neoplasm
  Gastric cancer
  Stomach cancer
• UniProt ID: RHG05_HUMAN
• PDB ID: 2EE4; 2EE5; 5U4V
• Pfam ID: PF01846 ; PF00620 ; PF16512 ; PF19518
• Sequence:
  MMAKNKEPRPPSYTISIVGLSGTEKDKGNCGVGKSCLCNRFVRSKADEYYPEHTSVLSTI
  DFGGRVVNNDHFLYWGDIIQNSEDGVECKIHVIEQTEFIDDQTFLPHRSTNLQPYIKRAA
  ASKLQSAEKLMYICTDQLGLEQDFEQKQMPEGKLNVDGFLLCIDVSQGCNRKFDDQLKFV
  NNLFVQLSKSKKPVIIAATKCDECVDHYLREVQAFASNKKNLLVVETSARFNVNIETCFT
  ALVQMLDKTRSKPKIIPYLDAYKTQRQLVVTATDKFEKLVQTVRDYHATWKTVSNKLKNH
  PDYEEYINLEGTRKARNTFSKHIEQLKQEHIRKRREEYINTLPRAFNTLLPNLEEIEHLN
  WSEALKLMEKRADFQLCFVVLEKTPWDETDHIDKINDRRIPFDLLSTLEAEKVYQNHVQH
  LISEKRRVEMKEKFKKTLEKIQFISPGQPWEEVMCFVMEDEAYKYITEADSKEVYGRHQR
  EIVEKAKEEFQEMLFEHSELFYDLDLNATPSSDKMSEIHTVLSEEPRYKALQKLAPDRES
  LLLKHIGFVYHPTKETCLSGQNCTDIKVEQLLASSLLQLDHGRLRLYHDSTNIDKVNLFI
  LGKDGLAQELANEIRTQSTDDEYALDGKIYELDLRPVDAKSPYFLSQLWTAAFKPHGCFC
  VFNSIESLSFIGEFIGKIRTEASQIRKDKYMANLPFTLILANQRDSISKNLPILRHQGQQ
  LANKLQCPFVDVPAGTYPRKFNETQIKQALRGVLESVKHNLDVVSPIPANKDLSEADLRI
  VMCAMCGDPFSVDLILSPFLDSHSCSAAQAGQNNSLMLDKIIGEKRRRIQITILSYHSSI
  GVRKDELVHGYILVYSAKRKASMGMLRAFLSEVQDTIPVQLVAVTDSQADFFENEAIKEL
  MTEGEHIATEITAKFTALYSLSQYHRQTEVFTLFFSDVLEKKNMIENSYLSDNTRESTHQ
  SEDVFLPSPRDCFPYNNYPDSDDDTEAPPPYSPIGDDVQLLPTPSDRSRYRLDLEGNEYP
  IHSTPNCHDHERNHKVPPPIKPKPVVPKTNVKKLDPNLLKTIEAGIGKNPRKQTSRVPLA
  HPEDMDPSDNYAEPIDTIFKQKGYSDEIYVVPDDSQNRIKIRNSFVNNTQGDEENGFSDR
  TSKSHGERRPSKYKYKSKTLFSKAKSYYRRTHSDASDDEAFTTSKTKRKGRHRGSEEDPL
  LSPVETWKGGIDNPAITSDQELDDKKMKKKTHKVKEDKKQKKKTKNFNPPTRRNWESNYF
  GMPLQDLVTAEKPIPLFVEKCVEFIEDTGLCTEGLYRVSGNKTDQDNIQKQFDQDHNINL
  VSMEVTVNAVAGALKAFFADLPDPLIPYSLHPELLEAAKIPDKTERLHALKEIVKKFHPV
  NYDVFRYVITHLNRVSQQHKINLMTADNLSICFWPTLMRPDFENREFLSTTKIHQSVVET
  FIQQCQFFFYNGEIVETTNIVAPPPPSNPGQLVEPMVPLQLPPPLQPQLIQPQLQTDPLG
  II
• Function: GTPase-activating protein for Rho family members.
• Tissue Specificity: Detected in skin fibroblasts (at protein level) .
• KEGG Pathway:
  Focal adhesion (hsa04510)
  Leukocyte transendothelial migration (hsa04670)
• Reactome Pathway:
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOG GTPase cycle (R-HSA-9013408)
  RHOJ GTPase cycle (R-HSA-9013409)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOF GTPase cycle (R-HSA-9035034)
  RND3 GTPase cycle (R-HSA-9696264)
  RND2 GTPase cycle (R-HSA-9696270)
  RND1 GTPase cycle (R-HSA-9696273)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Lung neoplasm	DISVARNB	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[5]
Gastric cancer	DISXGOUK	Limited	Biomarker	[6]
Stomach cancer	DISKIJSX	Limited	Biomarker	[6]

18 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 5 (ARHGAP5).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[15]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[23]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Rho GTPase-activating protein 5 (ARHGAP5).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rho GTPase-activating protein 5 (ARHGAP5).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Rho GTPase-activating protein 5 (ARHGAP5).	[20]

References

• [1] P190-B, a Rho-GTPase-activating protein, is differentially expressed in terminal end buds and breast cancer.Cell Growth Differ. 2000 Jul;11(7):343-54.
• [2] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [3] A novel amplification target, ARHGAP5, promotes cell spreading and migration by negatively regulating RhoA in Huh-7 hepatocellular carcinoma cells.Cancer Lett. 2009 Mar 8;275(1):27-34. doi: 10.1016/j.canlet.2008.09.036. Epub 2008 Nov 8.
• [4] Downregulation of miR-486-5p contributes to tumor progression and metastasis by targeting protumorigenic ARHGAP5 in lung cancer.Oncogene. 2014 Feb 27;33(9):1181-9. doi: 10.1038/onc.2013.42. Epub 2013 Mar 11.
• [5] SIRT1 suppresses the migration and invasion of gastric cancer by regulating ARHGAP5 expression.Cell Death Dis. 2018 Sep 24;9(10):977. doi: 10.1038/s41419-018-1033-8.
• [6] Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer.Cell Death Dis. 2019 May 16;10(6):383. doi: 10.1038/s41419-019-1585-2.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [12] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [15] 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.
• [16] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [19] 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.
• [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] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Lactic acid induced microRNA-744 enhances motility of SiHa cervical cancer cells through targeting ARHGAP5. Chem Biol Interact. 2019 Jan 25;298:86-95. doi: 10.1016/j.cbi.2018.10.027. Epub 2018 Nov 10.
• [24] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.