Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTU94AU)

• DOT Name: Rho GTPase-activating protein 12 (ARHGAP12)
• Synonyms: Rho-type GTPase-activating protein 12
• Gene Name: ARHGAP12
• Related Disease: Chronic obstructive pulmonary disease
• UniProt ID: RHG12_HUMAN
• Pfam ID: PF00169 ; PF00620 ; PF16618 ; PF00018 ; PF00397
• Sequence:
  MKMADRSGKIIPGQVYIEVEYDYEYEAKDRKIVIKQGERYILVKKTNDDWWQVKPDENSK
  AFYVPAQYVKEVTRKALMPPVKQVAGLPNNSTKIMQSLHLQRSTENVNKLPELSSFGKPS
  SSVQGTGLIRDANQNFGPSYNQGQTVNLSLDLTHNNGKFNNDSHSPKVSSQNRTRSFGHF
  PGPEFLDVEKTSFSQEQSCDSAGEGSERIHQDSESGDELSSSSTEQIRATTPPNQGRPDS
  PVYANLQELKISQSALPPLPGSPAIQINGEWETHKDSSGRCYYYNRGTQERTWKPPRWTR
  DASISKGDFQNPGDQELLSSEENYYSTSYSQSDSQCGSPPRGWSEELDERGHTLYTSDYT
  NEKWLKHVDDQGRQYYYSADGSRSEWELPKYNASSQQQREIIKSRSLDRRLQEPIVLTKW
  RHSTIVLDTNDKESPTASKPCFPENESSPSSPKHQDTASSPKDQEKYGLLNVTKIAENGK
  KVRKNWLSSWAVLQGSSLLFTKTQGSSTSWFGSNQSKPEFTVDLKGATIEMASKDKSSKK
  NVFELKTRQGTELLIQSDNDTVINDWFKVLSSTINNQAVETDEGIEEEIPDSPGIEKHDK
  EKEQKDPKKLRSFKVSSIDSSEQKKTKKNLKKFLTRRPTLQAVREKGYIKDQVFGSNLAN
  LCQRENGTVPKFVKLCIEHVEEHGLDIDGIYRVSGNLAVIQKLRFAVNHDEKLDLNDSKW
  EDIHVITGALKMFFRELPEPLFTFNHFNDFVNAIKQEPRQRVAAVKDLIRQLPKPNQDTM
  QILFRHLRRVIENGEKNRMTYQSIAIVFGPTLLKPEKETGNIAVHTVYQNQIVELILLEL
  SSIFGR
• Function: GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
• Reactome Pathway:
  RHOD GTPase cycle (R-HSA-9013405)
  RHOV GTPase cycle (R-HSA-9013424)
  RHOF GTPase cycle (R-HSA-9035034)
  RAC1 GTPase cycle (R-HSA-9013149)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Rho GTPase-activating protein 12 (ARHGAP12).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho GTPase-activating protein 12 (ARHGAP12).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho GTPase-activating protein 12 (ARHGAP12).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho GTPase-activating protein 12 (ARHGAP12).	[5]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Rho GTPase-activating protein 12 (ARHGAP12).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho GTPase-activating protein 12 (ARHGAP12).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rho GTPase-activating protein 12 (ARHGAP12).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rho GTPase-activating protein 12 (ARHGAP12).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rho GTPase-activating protein 12 (ARHGAP12).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho GTPase-activating protein 12 (ARHGAP12).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rho GTPase-activating protein 12 (ARHGAP12).	[10]

References

• [1] Exploring the cross-phenotype network region of disease modules reveals concordant and discordant pathways between chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.Hum Mol Genet. 2019 Jul 15;28(14):2352-2364. doi: 10.1093/hmg/ddz069.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] 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.
• [5] 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.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.