Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHJ1Y4I)

• DOT Name: Rho guanine nucleotide exchange factor 10 (ARHGEF10)
• Gene Name: ARHGEF10
• Related Disease:
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
  Autism spectrum disorder
  Bipolar disorder
  Chagas disease
  Charcot marie tooth disease
  Depression
  Multiple sclerosis
  Stroke
  Alopecia
  High blood pressure
  Autosomal dominant slowed nerve conduction velocity
  Hereditary neuropathy with liability to pressure palsies
  Neoplasm
  Peripheral neuropathy
• UniProt ID: ARHGA_HUMAN
• Pfam ID: PF19057 ; PF00621 ; PF19056
• Sequence:
  MRPPGFLSRAPSLNRAERGIWSCSMDQREPLPPAPAENEMKYDTNNNEEEEGEQFDFDSG
  DEIPEADRQAPSAPETGGAGASEAPAPTGGEDGAGAETTPVAEPTKLVLPMKVNPYSVID
  ITPFQEDQPPTPVPSAEEENVGLHVPCGYLVPVPCGYAVPSNLPLLLPAYSSPVIICATS
  LDEEAETPEVTEDRQPNSLSSEEPPTSEDQVGREDSALARWAADPANTAWMENPEEAIYD
  DVPRENSDSEPDEMIYDDVENGDEGGNSSLEYGWSSSEFESYEEQSDSECKNGIPRSFLR
  SNHKKQLSHDLTRLKEHYEKKMRDLMASTVGVVEIQQLRQKHELKMQKLVKAAKDGTKDG
  LERTRAAVKRGRSFIRTKSLIAQDHRSSLEEEQNLFIDVDCKHPEAILTPMPEGLSQQQV
  VRRYILGSVVDSEKNYVDALKRILEQYEKPLSEMEPKVLSERKLKTVFYRVKEILQCHSL
  FQIALASRVSEWDSVEMIGDVFVASFSKSMVLDAYSEYVNNFSTAVAVLKKTCATKPAFL
  EFLKQEQEASPDRTTLYSLMMKPIQRFPQFILLLQDMLKNTSKGHPDRLPLQMALTELET
  LAEKLNERKRDADQRCEVKQIAKAINERYLNKLLSSGSRYLIRSDDMIETVYNDRGEIVK
  TKERRVFMLNDVLMCATVSSRPSHDSRVMSSQRYLLKWSVPLGHVDAIEYGSSAGTGEHS
  RHLAVHPPESLAVVANAKPNKVYMGPGQLYQDLQNLLHDLNVIGQITQLIGNLKGNYQNL
  NQSVAHDWTSGLQRLILKKEDEIRAADCCRIQLQLPGKQDKSGRPTFFTAVFNTFTPAIK
  ESWVNSLQMAKLALEEENHMGWFCVEDDGNHIKKEKHPLLVGHMPVMVAKQQEFKIECAA
  YNPEPYLNNESQPDSFSTAHGFLWIGSCTHQMGQIAIVSFQNSTPKVIECFNVESRILCM
  LYVPVEEKRREPGAPPDPETPAVRASDVPTICVGTEEGSISIYKSSQGSKKVRLQHFFTP
  EKSTVMSLACTSQSLYAGLVNGAVASYARAPDGSWDSEPQKVIKLGVLPVRSLLMMEDTL
  WAASGGQVFIISVETHAVEGQLEAHQEEGMVISHMAVSGVGIWIAFTSGSTLRLFHTETL
  KHLQDINIATPVHNMLPGHQRLSVTSLLVCHGLLMVGTSLGVLVALPVPRLQGIPKVTGR
  GMVSYHAHNSPVKFIVLATALHEKDKDKSRDSLAPGPEPQDEDQKDALPSGGAGSSLSQG
  DPDAAIWLGDSLGSMTQKSDLSSSSGSLSLSHGSSSLEHRSEDSTIYDLLKDPVSLRSKA
  RRAKKAKASSALVVCGGQGHRRVHRKARQPHQEELAPTVMVWQIPLLNI
• Function: May play a role in developmental myelination of peripheral nerves.
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Matthew-Wood syndrome	DISA7HR7	Definitive	Biomarker	[1]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[1]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Chagas disease	DIS8KNVF	Strong	Biomarker	[4]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[5]
Depression	DIS3XJ69	Strong	Biomarker	[3]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[6]
Stroke	DISX6UHX	Strong	Genetic Variation	[7]
Alopecia	DIS37HU4	moderate	Altered Expression	[8]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[7]
Autosomal dominant slowed nerve conduction velocity	DISJJR7T	Supportive	Autosomal dominant	[9]
Hereditary neuropathy with liability to pressure palsies	DISY0X1V	Limited	Biomarker	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[1]
Peripheral neuropathy	DIS7KN5G	Limited	Autosomal dominant	[11]

4 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 guanine nucleotide exchange factor 10 (ARHGEF10).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[17]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[13]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[13]
Ifosfamide	DMCT3I8	Approved	Ifosfamide affects the expression of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[13]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Rho guanine nucleotide exchange factor 10 (ARHGEF10).	[13]

References

• [1] Rho guanine nucleotide exchange factor ARHGEF10 is a putative tumor suppressor in pancreatic ductal adenocarcinoma.Oncogene. 2020 Jan;39(2):308-321. doi: 10.1038/s41388-019-0985-1. Epub 2019 Sep 2.
• [2] Impairment of social behaviors in Arhgef10 knockout mice.Mol Autism. 2018 Feb 13;9:11. doi: 10.1186/s13229-018-0197-5. eCollection 2018.
• [3] Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer.Mol Psychiatry. 2009 Jun;14(6):563-89. doi: 10.1038/mp.2009.2. Epub 2009 Feb 10.
• [4] Genes of the cGMP-PKG-Ca(2+) signaling pathway are alternatively spliced in cardiomyopathy: Role of RBFOX2.Biochim Biophys Acta Mol Basis Dis. 2020 Mar 1;1866(3):165620. doi: 10.1016/j.bbadis.2019.165620. Epub 2019 Nov 25.
• [5] Involvement of Charcot-Marie-Tooth disease gene mitofusin 2 expression in paclitaxel-induced mechanical allodynia in rats.Neurosci Lett. 2017 Jul 13;653:337-340. doi: 10.1016/j.neulet.2017.05.069. Epub 2017 Jun 3.
• [6] A genome-wide association study of brain lesion distribution in multiple sclerosis.Brain. 2013 Apr;136(Pt 4):1012-24. doi: 10.1093/brain/aws363. Epub 2013 Feb 13.
• [7] ARHGEF10 gene polymorphism is closely associated with the risk of ischemic stroke in Northern Han Chinese population.Neurol Res. 2017 Feb;39(2):158-164. doi: 10.1080/01616412.2016.1263175. Epub 2016 Dec 9.
• [8] Taking advantage from phenotype variability in a local animal genetic resource: identification of genomic regions associated with the hairless phenotype in Casertana pigs.Anim Genet. 2018 Aug;49(4):321-325. doi: 10.1111/age.12665. Epub 2018 Apr 19.
• [9] Slowed conduction and thin myelination of peripheral nerves associated with mutant rho Guanine-nucleotide exchange factor 10. Am J Hum Genet. 2003 Oct;73(4):926-32. doi: 10.1086/378159. Epub 2003 Aug 19.
• [10] Clinical, electrophysiological and magnetic resonance findings in a family with hereditary neuropathy with liability to pressure palsies caused by a novel PMP22 mutation.Neuromuscul Disord. 2014 Jan;24(1):56-62. doi: 10.1016/j.nmd.2013.09.005. Epub 2013 Sep 13.
• [11] 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.
• [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] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [14] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [15] 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.
• [16] 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.
• [17] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [18] 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.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.