Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM196M3)

• DOT Name: N-chimaerin (CHN1)
• Synonyms: A-chimaerin; Alpha-chimerin; N-chimerin; NC; Rho GTPase-activating protein 2
• Gene Name: CHN1
• Related Disease:
  Chondrosarcoma
  Adolescent meningitis
  Duane retraction syndrome 2
  Hepatitis E virus infection
  Liver failure
  Prion disease
  Duane retraction syndrome
  Enterovirus infection
  Lung cancer
  Lung carcinoma
  Neuroblastoma
  Ocular motility disease
• UniProt ID: CHIN_HUMAN
• PDB ID: 2OSA; 3CXL
• Pfam ID: PF00130 ; PF00620 ; PF00017
• Sequence:
  MALTLFDTDEYRPPVWKSYLYQLQQEAPHPRRITCTCEVENRPKYYGREFHGMISREAAD
  QLLIVAEGSYLIRESQRQPGTYTLALRFGSQTRNFRLYYDGKHFVGEKRFESIHDLVTDG
  LITLYIETKAAEYIAKMTINPIYEHVGYTTLNREPAYKKHMPVLKETHDERDSTGQDGVS
  EKRLTSLVRRATLKENEQIPKYEKIHNFKVHTFRGPHWCEYCANFMWGLIAQGVKCADCG
  LNVHKQCSKMVPNDCKPDLKHVKKVYSCDLTTLVKAHTTKRPMVVDMCIREIESRGLNSE
  GLYRVSGFSDLIEDVKMAFDRDGEKADISVNMYEDINIITGALKLYFRDLPIPLITYDAY
  PKFIESAKIMDPDEQLETLHEALKLLPPAHCETLRYLMAHLKRVTLHEKENLMNAENLGI
  VFGPTLMRSPELDAMAALNDIRYQRLVVELLIKNEDILF
• Function: GTPase-activating protein for p21-rac and a phorbol ester receptor. Involved in the assembly of neuronal locomotor circuits as a direct effector of EPHA4 in axon guidance.
• Tissue Specificity: In neurons in brain regions that are involved in learning and memory processes.
• Reactome Pathway:
  RAC1 GTPase cycle (R-HSA-9013149)
  CDC42 GTPase cycle (R-HSA-9013148)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chondrosarcoma	DIS4I7JB	Definitive	Genetic Variation	[1]
Adolescent meningitis	DISYHNYB	Strong	Biomarker	[2]
Duane retraction syndrome 2	DISE6LRF	Strong	Autosomal dominant	[3]
Hepatitis E virus infection	DIS0TXIR	Strong	Genetic Variation	[4]
Liver failure	DISLGEL6	Strong	Genetic Variation	[5]
Prion disease	DISOUMB0	Strong	Genetic Variation	[6]
Duane retraction syndrome	DISOEBK2	Supportive	Autosomal dominant	[7]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[8]
Lung cancer	DISCM4YA	Limited	Biomarker	[9]
Lung carcinoma	DISTR26C	Limited	Biomarker	[9]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[10]
Ocular motility disease	DISEEIHX	Limited	Genetic Variation	[11]

12 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 N-chimaerin (CHN1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of N-chimaerin (CHN1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of N-chimaerin (CHN1).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of N-chimaerin (CHN1).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of N-chimaerin (CHN1).	[16]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of N-chimaerin (CHN1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of N-chimaerin (CHN1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of N-chimaerin (CHN1).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of N-chimaerin (CHN1).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of N-chimaerin (CHN1).	[23]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of N-chimaerin (CHN1).	[24]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of N-chimaerin (CHN1).	[25]

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 affects the methylation of N-chimaerin (CHN1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of N-chimaerin (CHN1).	[20]

References

• [1] Fluorescence in situ hybridization is a useful ancillary diagnostic tool for extraskeletal myxoid chondrosarcoma.Mod Pathol. 2008 Nov;21(11):1303-10. doi: 10.1038/modpathol.2008.114. Epub 2008 Jun 27.
• [2] Molecular characterization of a new human coxsackievirus B2 associated with severe hand-foot-mouth disease in Yunnan Province of China in 2012.Arch Virol. 2017 Jan;162(1):307-311. doi: 10.1007/s00705-016-3075-5. Epub 2016 Oct 1.
• [3] Two novel CHN1 mutations in 2 families with Duane retraction syndrome. Arch Ophthalmol. 2011 May;129(5):649-52. doi: 10.1001/archophthalmol.2011.84.
• [4] Different susceptibility and pathogenesis of rabbit genotype 3 hepatitis E virus (HEV-3) and human HEV-3 (JRC-HE3) in SPF rabbits.Vet Microbiol. 2017 Aug;207:1-6. doi: 10.1016/j.vetmic.2017.05.019. Epub 2017 May 29.
• [5] Hepatitis E virus genotype 4 isolated from a patient with liver failure: full-length sequence analysis showing potential determinants of virus pathogenesis.Arch Virol. 2013 Jan;158(1):165-72. doi: 10.1007/s00705-012-1488-3. Epub 2012 Sep 30.
• [6] Gene expression profiling on sheep brain reveals differential transcripts in scrapie-affected/not-affected animals.Brain Res. 2007 Apr 20;1142:217-22. doi: 10.1016/j.brainres.2007.01.033. Epub 2007 Jan 17.
• [7] Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. Science. 2008 Aug 8;321(5890):839-43. doi: 10.1126/science.1156121. Epub 2008 Jul 24.
• [8] Complete genome analysis of coxsackievirus A24 isolated in Yunnan, China, in 2013.Arch Virol. 2016 Jun;161(6):1705-9. doi: 10.1007/s00705-016-2792-0. Epub 2016 Mar 3.
• [9] Diagnosis by Volatile Organic Compounds in Exhaled Breath from Lung Cancer Patients Using Support Vector Machine Algorithm.Sensors (Basel). 2017 Feb 4;17(2):287. doi: 10.3390/s17020287.
• [10] The GTPase-activating protein n-chimaerin cooperates with Rac1 and Cdc42Hs to induce the formation of lamellipodia and filopodia.Mol Cell Biol. 1996 Sep;16(9):5069-80. doi: 10.1128/MCB.16.9.5069.
• [11] Analysis of the CHN1 gene in patients with various types of congenital ocular motility disorders.Graefes Arch Clin Exp Ophthalmol. 2010 Sep;248(9):1351-7. doi: 10.1007/s00417-010-1417-7. Epub 2010 Jun 10.
• [12] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [13] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [17] Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to Zidovudine. Environ Mol Mutagen. 2007 Apr-May;48(3-4):179-89. doi: 10.1002/em.20245.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] 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.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [24] 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.
• [25] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.