Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT81NKVT)

• DOT Name: MORC family CW-type zinc finger protein 3 (MORC3)
• Synonyms: Nuclear matrix protein 2; Zinc finger CW-type coiled-coil domain protein 3
• Gene Name: MORC3
• Related Disease:
  Acute myelogenous leukaemia
  Autoimmune disease
  Dermatomyositis
  Idiopathic inflammatory myopathy
  Myositis disease
  Skin disease
  Influenza
  Myopathy
  Nasopharyngeal carcinoma
• UniProt ID: MORC3_HUMAN
• PDB ID: 4QQ4; 5SVI; 5SVX; 5SVY; 6O1E; 6O5W
• Pfam ID: PF13589 ; PF17942 ; PF07496
• Sequence:
  MAAQPPRGIRLSALCPKFLHTNSTSHTWPFSAVAELIDNAYDPDVNAKQIWIDKTVINDH
  ICLTFTDNGNGMTSDKLHKMLSFGFSDKVTMNGHVPVGLYGNGFKSGSMRLGKDAIVFTK
  NGESMSVGLLSQTYLEVIKAEHVVVPIVAFNKHRQMINLAESKASLAAILEHSLFSTEQK
  LLAELDAIIGKKGTRIIIWNLRSYKNATEFDFEKDKYDIRIPEDLDEITGKKGYKKQERM
  DQIAPESDYSLRAYCSILYLKPRMQIILRGQKVKTQLVSKSLAYIERDVYRPKFLSKTVR
  ITFGFNCRNKDHYGIMMYHRNRLIKAYEKVGCQLRANNMGVGVVGIIECNFLKPTHNKQD
  FDYTNEYRLTITALGEKLNDYWNEMKVKKNTEYPLNLPVEDIQKRPDQTWVQCDACLKWR
  KLPDGMDQLPEKWYCSNNPDPQFRNCEVPEEPEDEDLVHPTYEKTYKKTNKEKFRIRQPE
  MIPRINAELLFRPTALSTPSFSSPKESVPRRHLSEGTNSYATRLLNNHQVPPQSEPESNS
  LKRRLSTRSSILNAKNRRLSSQFENSVYKGDDDDEDVIILEENSTPKPAVDHDIDMKSEQ
  SHVEQGGVQVEFVGDSEPCGQTGSTSTSSSRCDQGNTAATQTEVPSLVVKKEETVEDEID
  VRNDAVILPSCVEAEAKIHETQETTDKSADDAGCQLQELRNQLLLVTEEKENYKRQCHMF
  TDQIKVLQQRILEMNDKYVKKETCHQSTETDAVFLLESINGKSESPDHMVSQYQQALEEI
  ERLKKQCSALQHVKAECSQCSNNESKSEMDEMAVQLDDVFRQLDKCSIERDQYKSEVELL
  EMEKSQIRSQCEELKTEVEQLKSTNQQTATDVSTSSNIEESVNHMDGESLKLRSLRVNVG
  QLLAMIVPDLDLQQVNYDVDVVDEILGQVVEQMSEISST
• Function: Nuclear matrix protein which forms MORC3-NBs (nuclear bodies) via an ATP-dependent mechanism and plays a role in innate immunity by restricting different viruses through modulation of the IFN response. Mechanistically, possesses a primary antiviral function through a MORC3-regulated element that activates IFNB1, and this function is guarded by a secondary IFN-repressing function. Sumoylated MORC3-NBs associates with PML-NBs and recruits TP53 and SP100, thus regulating TP53 activity. Binds RNA in vitro. Histone methylation reader which binds to non-methylated (H3K4me0), monomethylated (H3K4me1), dimethylated (H3K4me2) and trimethylated (H3K4me3) 'Lys-4' on histone H3. The order of binding preference is H3K4me3 > H3K4me2 > H3K4me1 > H3K4me0 ; (Microbial infection) May be required for influenza A transcription during viral infection.
• Tissue Specificity: Expressed in heart, placenta, skeletal muscle, brain, pancreas, lung, liver, but not kidney.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Dermatomyositis	DIS50C5O	Strong	Biomarker	[3]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Biomarker	[4]
Myositis disease	DISCIXF0	Strong	Biomarker	[5]
Skin disease	DISDW8R6	Strong	Biomarker	[6]
Influenza	DIS3PNU3	moderate	Biomarker	[7]
Myopathy	DISOWG27	Limited	Biomarker	[8]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[8]

10 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 MORC family CW-type zinc finger protein 3 (MORC3).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MORC family CW-type zinc finger protein 3 (MORC3).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MORC family CW-type zinc finger protein 3 (MORC3).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MORC family CW-type zinc finger protein 3 (MORC3).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of MORC family CW-type zinc finger protein 3 (MORC3).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of MORC family CW-type zinc finger protein 3 (MORC3).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of MORC family CW-type zinc finger protein 3 (MORC3).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of MORC family CW-type zinc finger protein 3 (MORC3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of MORC family CW-type zinc finger protein 3 (MORC3).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of MORC family CW-type zinc finger protein 3 (MORC3).	[22]

4 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 MORC family CW-type zinc finger protein 3 (MORC3).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of MORC family CW-type zinc finger protein 3 (MORC3).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of MORC family CW-type zinc finger protein 3 (MORC3).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of MORC family CW-type zinc finger protein 3 (MORC3).	[21]

References

• [1] Anti-NXP2-antibody-positive immune-mediated necrotizing myopathy associated with acute myeloid leukemia: A case report.Medicine (Baltimore). 2018 Jul;97(28):e11501. doi: 10.1097/MD.0000000000011501.
• [2] Mechanism for autoinhibition and activation of the MORC3 ATPase.Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6111-6119. doi: 10.1073/pnas.1819524116. Epub 2019 Mar 8.
• [3] Perimysial microarteriopathy in dermatomyositis with anti-nuclear matrix protein-2 antibodies.Eur J Neurol. 2020 Mar;27(3):514-521. doi: 10.1111/ene.14097. Epub 2019 Oct 25.
• [4] Association of anti-nuclear matrix protein 2 antibody with complications in patients with idiopathic inflammatory myopathies: A meta-analysis of 20 cohorts.Clin Immunol. 2019 Jan;198:11-18. doi: 10.1016/j.clim.2018.11.008. Epub 2018 Nov 13.
• [5] Current understanding and recent advances in myositis-specific and -associated autoantibodies detected in patients with dermatomyositis.Expert Rev Clin Immunol. 2020 Jan;16(1):79-89. doi: 10.1080/1744666X.2019.1699059. Epub 2019 Dec 8.
• [6] Cutaneous and Systemic Findings Associated With Nuclear Matrix Protein 2 Antibodies in Adult Dermatomyositis Patients.Arthritis Care Res (Hoboken). 2017 Dec;69(12):1909-1914. doi: 10.1002/acr.23210. Epub 2017 Nov 2.
• [7] MORC3 Is a Target of the Influenza A Viral Protein NS1.Structure. 2019 Jun 4;27(6):1029-1033.e3. doi: 10.1016/j.str.2019.03.015. Epub 2019 Apr 18.
• [8] Calcinosis and malignancy are rare in Chinese adult patients with myositis and nuclear matrix protein 2 antibodies identified by an unlabeled immunoprecipitation assay.Clin Rheumatol. 2018 Oct;37(10):2731-2739. doi: 10.1007/s10067-018-4216-x. Epub 2018 Jul 23.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.