Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJNHX96)

• DOT Name: Rho GTPase-activating protein 9 (ARHGAP9)
• Synonyms: Rho-type GTPase-activating protein 9
• Gene Name: ARHGAP9
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Coronary vasospasm
  Glioma
  Liver cancer
  Metastatic prostate carcinoma
  Neoplasm
  Polycystic ovarian syndrome
  Hepatocellular carcinoma
• UniProt ID: RHG09_HUMAN
• PDB ID: 2P0D; 2P0F; 2P0H
• Pfam ID: PF00169 ; PF00620 ; PF00018
• Sequence:
  MLSSRWWPSSWGILGLGPRSPPRGSQLCALYAFTYTGADGQQVSLAEGDRFLLLRKTNSD
  WWLARRLEAPSTSRPIFVPAAYMIEESIPSQSPTTVIPGQLLWTPGPKLFHGSLEELSQA
  LPSRAQASSEQPPPLPRKMCRSVSTDNLSPSLLKPFQEGPSGRSLSQEDLPSEASASTAG
  PQPLMSEPPVYCNLVDLRRCPRSPPPGPACPLLQRLDAWEQHLDPNSGRCFYINSLTGCK
  SWKPPRRSRSETNPGSMEGTQTLKRNNDVLQPQAKGFRSDTGTPEPLDPQGSLSLSQRTS
  QLDPPALQAPRPLPQLLDDPHEVEKSGLLNMTKIAQGGRKLRKNWGPSWVVLTGNSLVFY
  REPPPTAPSSGWGPAGSRPESSVDLRGAALAHGRHLSSRRNVLHIRTIPGHEFLLQSDHE
  TELRAWHRALRTVIERLVRWVEARREAPTGRDQGSGDRENPLELRLSGSGPAELSAGEDE
  EEESELVSKPLLRLSSRRSSIRGPEGTEQNRVRNKLKRLIAKRPPLQSLQERGLLRDQVF
  GCQLESLCQREGDTVPSFLRLCIAAVDKRGLDVDGIYRVSGNLAVVQKLRFLVDRERAVT
  SDGRYVFPEQPGQEGRLDLDSTEWDDIHVVTGALKLFLRELPQPLVPPLLLPHFRAALAL
  SESEQCLSQIQELIGSMPKPNHDTLRYLLEHLCRVIAHSDKNRMTPHNLGIVFGPTLFRP
  EQETSDPAAHALYPGQLVQLMLTNFTSLFP
• Function: GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Has a substantial GAP activity toward CDC42 and RAC1 and less toward RHOA. Has a role in regulating adhesion of hematopoietic cells to the extracellular matrix. Binds phosphoinositides, and has the highest affinity for phosphatidylinositol 3,4,5-trisphosphate, followed by phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 4,5-bisphosphate.
• Tissue Specificity: Predominantly expressed in peripheral blood leukocytes, spleen, and thymus.
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[3]
Coronary vasospasm	DISSHV10	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Liver cancer	DISDE4BI	Strong	Altered Expression	[3]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[8]

12 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 9 (ARHGAP9).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Rho GTPase-activating protein 9 (ARHGAP9).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Rho GTPase-activating protein 9 (ARHGAP9).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Rho GTPase-activating protein 9 (ARHGAP9).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Rho GTPase-activating protein 9 (ARHGAP9).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Rho GTPase-activating protein 9 (ARHGAP9).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Rho GTPase-activating protein 9 (ARHGAP9).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho GTPase-activating protein 9 (ARHGAP9).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho GTPase-activating protein 9 (ARHGAP9).	[16]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Rho GTPase-activating protein 9 (ARHGAP9).	[17]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Rho GTPase-activating protein 9 (ARHGAP9).	[18]
Choline	DM5D9YK	Investigative	Choline affects the expression of Rho GTPase-activating protein 9 (ARHGAP9).	[19]

References

• [1] Silencing ARHGAP9 correlates with the risk of breast cancer and inhibits the proliferation, migration, and invasion of breast cancer.J Cell Biochem. 2018 Sep;119(9):7747-7756. doi: 10.1002/jcb.27127. Epub 2018 Jun 15.
• [2] Bioinformatics analysis of potential therapeutic targets among ARHGAP genes in breast cancer.Oncol Lett. 2019 Dec;18(6):6017-6025. doi: 10.3892/ol.2019.10949. Epub 2019 Oct 2.
• [3] Ginsenoside Rg3 inhibits the migration and invasion of liver cancer cells by increasing the protein expression of ARHGAP9.Oncol Lett. 2019 Jan;17(1):965-973. doi: 10.3892/ol.2018.9701. Epub 2018 Nov 15.
• [4] Mutation of ARHGAP9 in patients with coronary spastic angina.J Hum Genet. 2010 Jan;55(1):42-9. doi: 10.1038/jhg.2009.120. Epub 2009 Nov 13.
• [5] Expression of CXC-motif-chemokine 12 and the receptor C-X-C receptor 4 in glioma and theeffect on peritumoral brain edema.Oncol Lett. 2018 Feb;15(2):2501-2507. doi: 10.3892/ol.2017.7547. Epub 2017 Dec 8.
• [6] Cysteine (C)-x-C receptor 4 undergoes transportin 1-dependent nuclear localization and remains functional at the nucleus of metastatic prostate cancer cells.PLoS One. 2013;8(2):e57194. doi: 10.1371/journal.pone.0057194. Epub 2013 Feb 28.
• [7] Pathway and network-based analysis of genome-wide association studies and RT-PCR validation in polycystic ovary syndrome.Int J Mol Med. 2017 Nov;40(5):1385-1396. doi: 10.3892/ijmm.2017.3146. Epub 2017 Sep 20.
• [8] ARHGAP9 suppresses the migration and invasion of hepatocellular carcinoma cells through up-regulating FOXJ2/E-cadherin.Cell Death Dis. 2018 Sep 11;9(9):916. doi: 10.1038/s41419-018-0976-0.
• [9] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] 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.
• [13] 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.
• [14] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [15] 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.
• [16] 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.
• [17] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [18] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.
• [19] Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not. Am J Clin Nutr. 2007 Jul;86(1):230-9. doi: 10.1093/ajcn/86.1.230.