Details of Drug Off-Target (DOT)

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

• DOT Name: Rho GTPase-activating protein 17 (ARHGAP17)
• Synonyms: Rho-type GTPase-activating protein 17; RhoGAP interacting with CIP4 homologs protein 1; RICH-1
• Gene Name: ARHGAP17
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Neoplasm
• UniProt ID: RHG17_HUMAN
• Pfam ID: PF03114 ; PF00620
• Sequence:
  MKKQFNRMKQLANQTVGRAEKTEVLSEDLLQIERRLDTVRSICHHSHKRLVACFQGQHGT
  DAERRHKKLPLTALAQNMQEASTQLEDSLLGKMLETCGDAENQLALELSQHEVFVEKEIV
  DPLYGIAEVEIPNIQKQRKQLARLVLDWDSVRARWNQAHKSSGTNFQGLPSKIDTLKEEM
  DEAGNKVEQCKDQLAADMYNFMAKEGEYGKFFVTLLEAQADYHRKALAVLEKTLPEMRAH
  QDKWAEKPAFGTPLEEHLKRSGREIALPIEACVMLLLETGMKEEGLFRIGAGASKLKKLK
  AALDCSTSHLDEFYSDPHAVAGALKSYLRELPEPLMTFNLYEEWTQVASVQDQDKKLQDL
  WRTCQKLPPQNFVNFRYLIKFLAKLAQTSDVNKMTPSNIAIVLGPNLLWARNEGTLAEMA
  AATSVHVVAVIEPIIQHADWFFPEEVEFNVSEAFVPLTTPSSNHSFHTGNDSDSGTLERK
  RPASMAVMEGDLVKKESFGVKLMDFQAHRRGGTLNRKHISPAFQPPLPPTDGSTVVPAGP
  EPPPQSSRAESSSGGGTVPSSAGILEQGPSPGDGSPPKPKDPVSAAVPAPGRNNSQIASG
  QNQPQAAAGSHQLSMGQPHNAAGPSPHTLRRAVKKPAPAPPKPGNPPPGHPGGQSSSGTS
  QHPPSLSPKPPTRSPSPPTQHTGQPPGQPSAPSQLSAPRRYSSSLSPIQAPNHPPPQPPT
  QATPLMHTKPNSQGPPNPMALPSEHGLEQPSHTPPQTPTPPSTPPLGKQNPSLPAPQTLA
  GGNPETAQPHAGTLPRPRPVPKPRNRPSVPPPPQPPGVHSAGDSSLTNTAPTASKIVTDS
  NSRVSEPHRSIFPEMHSDSASKDVPGRILLDIDNDTESTAL
• Function: Rho GTPase-activating protein involved in the maintenance of tight junction by regulating the activity of CDC42, thereby playing a central role in apical polarity of epithelial cells. Specifically acts as a GTPase activator for the CDC42 GTPase by converting it to an inactive GDP-bound state. The complex formed with AMOT acts by regulating the uptake of polarity proteins at tight junctions, possibly by deciding whether tight junction transmembrane proteins are recycled back to the plasma membrane or sent elsewhere. Participates in the Ca(2+)-dependent regulation of exocytosis, possibly by catalyzing GTPase activity of Rho family proteins and by inducing the reorganization of the cortical actin filaments. Acts as a GTPase activator in vitro for RAC1.
• Tissue Specificity: Ubiquitously expressed. Expressed at higher level in heart and placenta.
• KEGG Pathway: Tight junction (hsa04530)
• Reactome Pathway:
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOQ GTPase cycle (R-HSA-9013406)
  RAC3 GTPase cycle (R-HSA-9013423)
  CDC42 GTPase cycle (R-HSA-9013148)

Molecular Interaction Atlas (MIA) of This DOT

8 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]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[3]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[1]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[8]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[9]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[12]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Rho GTPase-activating protein 17 (ARHGAP17).	[16]

2 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 increases the methylation of Rho GTPase-activating protein 17 (ARHGAP17).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rho GTPase-activating protein 17 (ARHGAP17).	[13]

References

• [1] Tumor Suppressive Role of ARHGAP17 in Colon Cancer Through Wnt/-Catenin Signaling.Cell Physiol Biochem. 2018;46(5):2138-2148. doi: 10.1159/000489543. Epub 2018 Apr 28.
• [2] Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network.Int J Cancer. 2018 Dec 1;143(11):2905-2918. doi: 10.1002/ijc.31645. Epub 2018 Oct 9.
• [3] ARHGAP17 suppresses tumor progression and up-regulates P21 and P27 expression via inhibiting PI3K/AKT signaling pathway in cervical cancer.Gene. 2019 Apr 15;692:9-16. doi: 10.1016/j.gene.2019.01.004. Epub 2019 Jan 11.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [15] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.