Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXV053R)

• DOT Name: Rho GTPase-activating protein 4 (ARHGAP4)
• Synonyms: Rho-GAP hematopoietic protein C1; Rho-type GTPase-activating protein 4; p115
• Gene Name: ARHGAP4
• Related Disease:
  Ogden syndrome
  Diabetes insipidus, nephrogenic, X-linked
  Hepatocellular carcinoma
  HIV infectious disease
  Nephrogenic diabetes insipidus
  Coronary heart disease
  Systemic lupus erythematosus
  Intellectual disability
  Neoplasm
  Pancreatic cancer
  Schizophrenia
• UniProt ID: RHG04_HUMAN
• PDB ID: 2EPD
• Pfam ID: PF00611 ; PF00620 ; PF14604
• Sequence:
  MAAHGKLRRERGLQAEYETQVKEMRWQLSEQLRCLELQGELRRELLQELAEFMRRRAEVE
  LEYSRGLEKLAERFSSRGGRLGSSREHQSFRKEPSLLSPLHCWAVLLQHTRQQSRESAAL
  SEVLAGPLAQRLSHIAEDVGRLVKKSRDLEQQLQDELLEVVSELQTAKKTYQAYHMESVN
  AEAKLREAERQEEKRAGRSVPTTTAGATEAGPLRKSSLKKGGRLVEKRQAKFMEHKLKCT
  KARNEYLLSLASVNAAVSNYYLHDVLDLMDCCDTGFHLALGQVLRSYTAAESRTQASQVQ
  GLGSLEEAVEALDPPGDKAKVLEVHATVFCPPLRFDYHPHDGDEVAEICVEMELRDEILP
  RAQNIQSRLDRQTIETEEVNKTLKATLQALLEVVASDDGDVLDSFQTSPSTESLKSTSSD
  PGSRQAGRRRGQQQETETFYLTKLQEYLSGRSILAKLQAKHEKLQEALQRGDKEEQEVSW
  TQYTQRKFQKSRQPRPSSQYNQRLFGGDMEKFIQSSGQPVPLVVESCIRFINLNGLQHEG
  IFRVSGAQLRVSEIRDAFERGEDPLVEGCTAHDLDSVAGVLKLYFRSLEPPLFPPDLFGE
  LLASSELEATAERVEHVSRLLWRLPAPVLVVLRYLFTFLNHLAQYSDENMMDPYNLAVCF
  GPTLLPVPAGQDPVALQGRVNQLVQTLIVQPDRVFPPLTSLPGPVYEKCMAPPSASCLGD
  AQLESLGADNEPELEAEMPAQEDDLEGVVEAVACFAYTGRTAQELSFRRGDVLRLHERAS
  SDWWRGEHNGMRGLIPHKYITLPAGTEKQVVGAGLQTAGESGSSPEGLLASELVHRPEPC
  TSPEAMGPSGHRRRCLVPASPEQHVEVDKAVAQNMDSVFKELLGKTSVRQGLGPASTTSP
  SPGPRSPKAPPSSRLGRNKGFSRGPGAPASPSASHPQGLDTTPKPH
• Function: Inhibitory effect on stress fiber organization. May down-regulate Rho-like GTPase in hematopoietic cells.
• Tissue Specificity: Predominantly in hematopoietic cells (spleen, thymus and leukocytes); low levels in placenta, lung and various fetal tissues.
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ogden syndrome	DISLI754	Definitive	Genetic Variation	[1]
Diabetes insipidus, nephrogenic, X-linked	DISHUTO5	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
HIV infectious disease	DISO97HC	Strong	Biomarker	[4]
Nephrogenic diabetes insipidus	DISKNSJK	Strong	Genetic Variation	[5]
Coronary heart disease	DIS5OIP1	moderate	Biomarker	[6]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[7]
Intellectual disability	DISMBNXP	Limited	X-linked	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[9]
Pancreatic cancer	DISJC981	Limited	Biomarker	[10]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Rho GTPase-activating protein 4 (ARHGAP4).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho GTPase-activating protein 4 (ARHGAP4).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[17]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[23]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[24]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Rho GTPase-activating protein 4 (ARHGAP4).	[24]

References

• [1] Lessons learned from additional research analyses of unsolved clinical exome cases.Genome Med. 2017 Mar 21;9(1):26. doi: 10.1186/s13073-017-0412-6.
• [2] A novel contiguous gene deletion of AVPR2 and ARHGAP4 genes in male dizygotic twins with nephrogenic diabetes insipidus and intellectual disability.Am J Med Genet A. 2012 Oct;158A(10):2511-8. doi: 10.1002/ajmg.a.35591. Epub 2012 Sep 10.
• [3] Proteomic analysis of differentially expressed proteins in hepatitis B virus-related hepatocellular carcinoma tissues.J Exp Clin Cancer Res. 2009 Aug 28;28(1):122. doi: 10.1186/1756-9966-28-122.
• [4] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [5] Contiguous 22.1-kb deletion embracing AVPR2 and ARHGAP4 genes at novel breakpoints leads to nephrogenic diabetes insipidus in a Chinese pedigree.BMC Nephrol. 2018 Feb 2;19(1):26. doi: 10.1186/s12882-018-0825-5.
• [6] Identification of new genes differentially expressed in coronary artery disease by expression profiling.Physiol Genomics. 2003 Sep 29;15(1):65-74. doi: 10.1152/physiolgenomics.00181.2002.
• [7] A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus.Nat Genet. 2009 Nov;41(11):1228-33. doi: 10.1038/ng.468. Epub 2009 Oct 18.
• [8] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [9] Gene expression profiling of ameloblastoma and human tooth germ by means of a cDNA microarray.J Dent Res. 2002 Aug;81(8):525-30. doi: 10.1177/154405910208100805.
• [10] ARHGAP4 regulates the cell migration and invasion of pancreatic cancer by the HDAC2/-catenin signaling pathway.Carcinogenesis. 2019 Nov 25;40(11):1405-1414. doi: 10.1093/carcin/bgz067.
• [11] Common variants on Xq28 conferring risk of schizophrenia in Han Chinese.Schizophr Bull. 2014 Jul;40(4):777-86. doi: 10.1093/schbul/sbt104. Epub 2013 Sep 16.
• [12] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [13] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [18] Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin. Am J Respir Cell Mol Biol. 2004 May;30(5):662-70. doi: 10.1165/rcmb.2003-0267OC. Epub 2003 Nov 20.
• [19] 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.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [21] 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.
• [22] 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.
• [23] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [24] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.