Details of Drug Off-Target (DOT)

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

• DOT Name: Rho GTPase-activating protein 11A (ARHGAP11A)
• Synonyms: Rho-type GTPase-activating protein 11A
• Gene Name: ARHGAP11A
• Related Disease:
  Advanced cancer
  Breast cancer
  Colon cancer
  Hepatocellular carcinoma
  Breast carcinoma
  Intellectual disability
• UniProt ID: RHGBA_HUMAN
• PDB ID: 3EAP
• Pfam ID: PF00620
• Sequence:
  MWDQRLVRLALLQHLRAFYGIKVKGVRGQCDRRRHETAATEIGGKIFGVPFNALPHSAVP
  EYGHIPSFLVDACTSLEDHIHTEGLFRKSGSVIRLKALKNKVDHGEGCLSSAPPCDIAGL
  LKQFFRELPEPILPADLHEALLKAQQLGTEEKNKATLLLSCLLADHTVHVLRYFFNFLRN
  VSLRSSENKMDSSNLAVIFAPNLLQTSEGHEKMSSNTEKKLRLQAAVVQTLIDYASDIGR
  VPDFILEKIPAMLGIDGLCATPSLEGFEEGEYETPGEYKRKRRQSVGDFVSGALNKFKPN
  RTPSITPQEERIAQLSESPVILTPNAKRTLPVDSSHGFSSKKRKSIKHNFNFELLPSNLF
  NSSSTPVSVHIDTSSEGSSQSSLSPVLIGGNHLITAGVPRRSKRIAGKKVCRVESGKAGC
  FSPKISHKEKVRRSLRLKFNLGKNGREVNGCSGVNRYESVGWRLANQQSLKNRIESVKTG
  LLFSPDVDEKLPKKGSEKISKSEETLLTPERLVGTNYRMSWTGPNNSSFQEVDANEASSM
  VENLEVENSLEPDIMVEKSPATSCELTPSNLNNKHNSNITSSPLSGDENNMTKETLVKVQ
  KAFSESGSNLHALMNQRQSSVTNVGKVKLTEPSYLEDSPEENLFETNDLTIVESKEKYEH
  HTGKGEKCFSERDFSPLQTQTFNRETTIKCYSTQMKMEHEKDIHSNMPKDYLSKQEFSSD
  EEIKKQQSPKDKLNNKLKENENMMEGNLPKCAAHSKDEARSSFSQQSTCVVTNLSKPRPM
  RIAKQQSLETCEKTVSESSQMTEHRKVSDHIQWFNKLSLNEPNRIKVKSPLKFQRTPVRQ
  SVRRINSLLEYSRQPTGHKLASLGDTASPLVKSVSCDGALSSCIESASKDSSVSCIKSGP
  KEQKSMSCEESNIGAISKSSMELPSKSFLKMRKHPDSVNASLRSTTVYKQKILSDGQVKV
  PLDDLTNHDIVKPVVNNNMGISSGINNRVLRRPSERGRAWYKGSPKHPIGKTQLLPTSKP
  VDL
• Function: GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
• Reactome Pathway: RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Disputed	Altered Expression	[2]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[13]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[14]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[15]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[24]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[25]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[26]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Rho GTPase-activating protein 11A (ARHGAP11A).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Rho GTPase-activating protein 11A (ARHGAP11A).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Rho GTPase-activating protein 11A (ARHGAP11A).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho GTPase-activating protein 11A (ARHGAP11A).	[22]

References

• [1] Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo.PLoS One. 2013 Dec 30;8(12):e83629. doi: 10.1371/journal.pone.0083629. eCollection 2013.
• [2] PIWI-interacting RNA 021285 is involved in breast tumorigenesis possibly by remodeling the cancer epigenome.Carcinogenesis. 2015 Oct;36(10):1094-102. doi: 10.1093/carcin/bgv105. Epub 2015 Jul 25.
• [3] Blockade of ARHGAP11A reverses malignant progress via inactivating Rac1B in hepatocellular carcinoma.Cell Commun Signal. 2018 Dec 13;16(1):99. doi: 10.1186/s12964-018-0312-4.
• [4] Characterization of a 5.3 Mb deletion in 15q14 by comparative genomic hybridization using a whole genome "tiling path" BAC array in a girl with heart defect, cleft palate, and developmental delay.Am J Med Genet A. 2007 Jan 15;143A(2):172-8. doi: 10.1002/ajmg.a.31541.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [13] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [14] 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.
• [15] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [16] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [20] 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.
• [21] 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.
• [22] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [23] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [26] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [27] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.