Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0H2ZBZ)

• DOT Name: Rho GTPase-activating protein 1 (ARHGAP1)
• Synonyms: CDC42 GTPase-activating protein; GTPase-activating protein rhoGAP; Rho-related small GTPase protein activator; Rho-type GTPase-activating protein 1; p50-RhoGAP
• Gene Name: ARHGAP1
• Related Disease:
  Non-small-cell lung cancer
  Adult glioblastoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Cervical cancer
  Cervical carcinoma
  Diabetes insipidus, nephrogenic, X-linked
  Ewing sarcoma
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Linear skin defects with multiple congenital anomalies 1
  Liver cancer
  Lung cancer
  Lung carcinoma
  Malignant soft tissue neoplasm
  Neoplasm
  Nephrogenic diabetes insipidus
  Oculocerebrorenal syndrome
  Prostate adenocarcinoma
  Sarcoma
  Schizophrenia
  Triple negative breast cancer
  Advanced cancer
  Congenital glaucoma
  High blood pressure
  Intellectual disability
  Prostate cancer
  Prostate carcinoma
  X-linked intellectual disability
• UniProt ID: RHG01_HUMAN
• PDB ID: 1AM4; 1GRN; 1OW3; 1RGP; 1TX4; 2NGR; 5M6X; 5M70; 6R3V; 7QSC; 7QTM
• Pfam ID: PF13716 ; PF00620
• Sequence:
  MDPLSELQDDLTLDDTSEALNQLKLASIDEKNWPSDEMPDFPKSDDSKSSSPELVTHLKW
  DDPYYDIARHQIVEVAGDDKYGRKIIVFSACRMPPSHQLDHSKLLGYLKHTLDQYVESDY
  TLLYLHHGLTSDNKPSLSWLRDAYREFDRKYKKNIKALYIVHPTMFIKTLLILFKPLISF
  KFGQKIFYVNYLSELSEHVKLEQLGIPRQVLKYDDFLKSTQKSPATAPKPMPPRPPLPNQ
  QFGVSLQHLQEKNPEQEPIPIVLRETVAYLQAHALTTEGIFRRSANTQVVREVQQKYNMG
  LPVDFDQYNELHLPAVILKTFLRELPEPLLTFDLYPHVVGFLNIDESQRVPATLQVLQTL
  PEENYQVLRFLTAFLVQISAHSDQNKMTNTNLAVVFGPNLLWAKDAAITLKAINPINTFT
  KFLLDHQGELFPSPDPSGL
• Function: GTPase activator for the Rho, Rac and Cdc42 proteins, converting them to the putatively inactive GDP-bound state. Cdc42 seems to be the preferred substrate.
• Tissue Specificity: Ubiquitous.
• 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)
  RAC2 GTPase cycle (R-HSA-9013404)
  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)
  RND2 GTPase cycle (R-HSA-9696270)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[5]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[6]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[6]
Diabetes insipidus, nephrogenic, X-linked	DISHUTO5	Strong	Altered Expression	[7]
Ewing sarcoma	DISQYLV3	Strong	Altered Expression	[8]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Linear skin defects with multiple congenital anomalies 1	DISNYKBT	Strong	Biomarker	[10]
Liver cancer	DISDE4BI	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Altered Expression	[11]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[11]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Nephrogenic diabetes insipidus	DISKNSJK	Strong	Genetic Variation	[14]
Oculocerebrorenal syndrome	DIS8TEDY	Strong	Biomarker	[15]
Prostate adenocarcinoma	DISBZYU8	Strong	Biomarker	[2]
Sarcoma	DISZDG3U	Strong	Biomarker	[12]
Schizophrenia	DISSRV2N	Strong	Biomarker	[16]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[17]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[18]
Congenital glaucoma	DISHN3GO	moderate	Genetic Variation	[19]
High blood pressure	DISY2OHH	moderate	Biomarker	[20]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[21]
Prostate cancer	DISF190Y	Limited	Biomarker	[22]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[22]
X-linked intellectual disability	DISYJBY3	Limited	Genetic Variation	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[28]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[29]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[30]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[31]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[35]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Rho GTPase-activating protein 1 (ARHGAP1).	[36]

3 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 affects the methylation of Rho GTPase-activating protein 1 (ARHGAP1).	[33]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Rho GTPase-activating protein 1 (ARHGAP1).	[34]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Rho GTPase-activating protein 1 (ARHGAP1).	[34]

References

• [1] DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms.Mol Carcinog. 2008 May;47(5):326-37. doi: 10.1002/mc.20389.
• [2] ARHGAP21 is a RhoGAP for RhoA and RhoC with a role in proliferation and migration of prostate adenocarcinoma cells.Biochim Biophys Acta. 2013 Feb;1832(2):365-74. doi: 10.1016/j.bbadis.2012.11.010. Epub 2012 Nov 28.
• [3] The RhoGAP protein DLC-1 functions as a metastasis suppressor in breast cancer cells.Cancer Res. 2005 Jul 15;65(14):6042-53. doi: 10.1158/0008-5472.CAN-04-3043.
• [4] Chromosome 13q12 encoded Rho GTPase activating protein suppresses growth of breast carcinoma cells, and yeast two-hybrid screen shows its interaction with several proteins.Biochem Biophys Res Commun. 2004 Jan 16;313(3):654-65. doi: 10.1016/j.bbrc.2003.12.001.
• [5] Regulation of white and brown adipocyte differentiation by RhoGAP DLC1.PLoS One. 2017 Mar 30;12(3):e0174761. doi: 10.1371/journal.pone.0174761. eCollection 2017.
• [6] ARHGAP1 overexpression inhibits proliferation, migration and invasion of C-33A and SiHa cell lines.Onco Targets Ther. 2017 Feb 7;10:691-701. doi: 10.2147/OTT.S112223. eCollection 2017.
• [7] Immunological profile in a family with nephrogenic diabetes insipidus with a novel 11 kb deletion in AVPR2 and ARHGAP4 genes.BMC Med Genet. 2008 May 20;9:42. doi: 10.1186/1471-2350-9-42.
• [8] miR-130b directly targets ARHGAP1 to drive activation of a metastatic CDC42-PAK1-AP1 positive feedback loop in Ewing sarcoma.Int J Cancer. 2017 Nov 15;141(10):2062-2075. doi: 10.1002/ijc.30909. Epub 2017 Aug 8.
• [9] Deleted in liver cancer (DLC) 2 encodes a RhoGAP protein with growth suppressor function and is underexpressed in hepatocellular carcinoma.J Biol Chem. 2003 Mar 21;278(12):10824-30. doi: 10.1074/jbc.M208310200. Epub 2003 Jan 16.
• [10] Functional analysis of ARHGAP6, a novel GTPase-activating protein for RhoA.Hum Mol Genet. 2000 Mar 1;9(4):477-88. doi: 10.1093/hmg/9.4.477.
• [11] ARHGAP6 regulates the proliferation, migration and invasion of lung cancer cells.Oncol Rep. 2019 Apr;41(4):2281-2888. doi: 10.3892/or.2019.7031. Epub 2019 Feb 25.
• [12] Expression profiles of signal transduction genes in ex vivo drug-resistant pediatric acute lymphoblastic leukemia.Anticancer Res. 2012 Feb;32(2):503-6.
• [13] DLC1 SAM domain-binding peptides inhibit cancer cell growth and migration by inactivating RhoA.J Biol Chem. 2020 Jan 10;295(2):645-656. doi: 10.1074/jbc.RA119.011929. Epub 2019 Dec 5.
• [14] Two novel types of contiguous gene deletion of the AVPR2 and ARHGAP4 genes in unrelated Japanese kindreds with nephrogenic diabetes insipidus.Hum Mutat. 2002 Jan;19(1):23-9. doi: 10.1002/humu.10011.
• [15] Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1.Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3511-6. doi: 10.1073/pnas.0914658107. Epub 2010 Feb 2.
• [16] The p250GAP gene is associated with risk for schizophrenia and schizotypal personality traits.PLoS One. 2012;7(4):e35696. doi: 10.1371/journal.pone.0035696. Epub 2012 Apr 18.
• [17] 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.
• [18] p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity.J Cell Biol. 2018 Sep 3;217(9):3183-3201. doi: 10.1083/jcb.201710058. Epub 2018 Jun 22.
• [19] Ocular Pathology of Oculocerebrorenal Syndrome of Lowe: Novel Mutations and Genotype-Phenotype Analysis.Sci Rep. 2017 May 4;7(1):1442. doi: 10.1038/s41598-017-01447-3.
• [20] The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension.Nat Commun. 2013;4:2910. doi: 10.1038/ncomms3910.
• [21] Lowe syndrome protein OCRL1 interacts with Rac GTPase in the trans-Golgi network.Hum Mol Genet. 2003 Oct 1;12(19):2449-56. doi: 10.1093/hmg/ddg250. Epub 2003 Jul 29.
• [22] BMCC1 is an AP-2 associated endosomal protein in prostate cancer cells.PLoS One. 2013 Sep 6;8(9):e73880. doi: 10.1371/journal.pone.0073880. eCollection 2013.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [27] 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.
• [28] 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.
• [29] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [30] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [31] 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.
• [32] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [33] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [34] 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.
• [35] 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.
• [36] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.