Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYMJP6H)

• DOT Name: Rho GTPase-activating protein 18 (ARHGAP18)
• Synonyms: MacGAP; Rho-type GTPase-activating protein 18
• Gene Name: ARHGAP18
• Related Disease:
  Aortic aneurysm
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Fuchs' endothelial dystrophy
  Invasive breast carcinoma
  Neoplasm
  Triple negative breast cancer
  Bladder cancer
  Urinary bladder cancer
  Hepatocellular carcinoma
  Schizophrenia
• UniProt ID: RHG18_HUMAN
• Pfam ID: PF00620
• Sequence:
  MSWLSSSQGVVLTAYHPSGKDQTVGNSHAKAGEEATSSRRYGQYTMNQESTTIKVMEKPP
  FDRSISQDSLDELSMEDYWIELENIKKSSENSQEDQEVVVVKEPDEGELEEEWLKEAGLS
  NLFGESAGDPQESIVFLSTLTRTQAAAVQKRVETVSQTLRKKNKQYQIPDVRDIFAQQRE
  SKETAPGGTESQSLRTNENKYQGRDDEASNLVGEEKLIPPEETPAPETDINLEVSFAEQA
  LNQKESSKEKIQKSKGDDATLPSFRLPKDKTGTTRIGDLAPQDMKKVCHLALIELTALYD
  VLGIELKQQKAVKIKTKDSGLFCVPLTALLEQDQRKVPGMRIPLIFQKLISRIEERGLET
  EGLLRIPGAAIRIKNLCQELEAKFYEGTFNWESVKQHDAASLLKLFIRELPQPLLSVEYL
  KAFQAVQNLPTKKQQLQALNLLVILLPDANRDTLKALLEFLQRVIDNKEKNKMTVMNVAM
  VMAPNLFMCHALGLKSSEQREFVMAAGTANTMHLLIKYQKLLWTIPKFIVNQVRKQNTEN
  HKKDKRAMKKLLKKMAYDREKYEKQDKSTNDADVPQGVIRVQAPHLSKVSMAIQLTEELK
  ASDVLARFLSQESGVAQTLKKGEVFLYEIGGNIGERCLDDDTYMKDLYQLNPNAEWVIKS
  KPL
• Function: Rho GTPase activating protein that suppresses F-actin polymerization by inhibiting Rho. Rho GTPase activating proteins act by converting Rho-type GTPases to an inactive GDP-bound state. Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation. Acts downstream of YAP1 and inhibits actin polymerization, which in turn reduces nuclear localization of YAP1. Regulates cell shape, spreading, and migration.
• Reactome Pathway:
  RHOC GTPase cycle (R-HSA-9013106)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aortic aneurysm	DISQ5KRA	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Fuchs' endothelial dystrophy	DISL7TXC	Strong	Altered Expression	[4]
Invasive breast carcinoma	DISANYTW	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[5]
Bladder cancer	DISUHNM0	moderate	Biomarker	[6]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[7]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[8]

25 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 Rho GTPase-activating protein 18 (ARHGAP18).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[20]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[22]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[23]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[24]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[20]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[25]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[26]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[32]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rho GTPase-activating protein 18 (ARHGAP18).	[25]

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 18 (ARHGAP18).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Rho GTPase-activating protein 18 (ARHGAP18).	[30]

References

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• [2] ARHGAP18: A Flow-Responsive Gene That Regulates Endothelial Cell Alignment and Protects Against Atherosclerosis.J Am Heart Assoc. 2019 Jan 22;8(2):e010057. doi: 10.1161/JAHA.118.010057.
• [3] Rho-GTPase activating-protein 18: a biomarker associated with good prognosis in invasive breast cancer.Br J Cancer. 2017 Oct 10;117(8):1176-1184. doi: 10.1038/bjc.2017.261. Epub 2017 Aug 22.
• [4] Transcript profile of cellular senescence-related genes in Fuchs endothelial corneal dystrophy.Exp Eye Res. 2014 Dec;129:13-7. doi: 10.1016/j.exer.2014.10.011. Epub 2014 Oct 11.
• [5] ARHGAP18 Downregulation by miR-200b Suppresses Metastasis of Triple-Negative Breast Cancer by Enhancing Activation of RhoA.Cancer Res. 2017 Aug 1;77(15):4051-4064. doi: 10.1158/0008-5472.CAN-16-3141. Epub 2017 Jun 15.
• [6] A novel cellular senescence gene, SENEX, is involved in peripheral regulatory T cells accumulation in aged urinary bladder cancer.PLoS One. 2014 Feb 5;9(2):e87774. doi: 10.1371/journal.pone.0087774. eCollection 2014.
• [7] LncRNA CDKN2BAS predicts poor prognosis in patients with hepatocellular carcinoma and promotes metastasis via the miR-153-5p/ARHGAP18 signaling axis.Aging (Albany NY). 2018 Nov 29;10(11):3371-3381. doi: 10.18632/aging.101645.
• [8] Association of ARHGAP18 polymorphisms with schizophrenia in the Chinese-Han population.PLoS One. 2017 Apr 6;12(4):e0175209. doi: 10.1371/journal.pone.0175209. eCollection 2017.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] 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.
• [17] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [18] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [19] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [20] 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.
• [21] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [22] 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.
• [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] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [27] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [28] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] 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.