Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTESJ5S7)

• DOT Name: Matrin-3 (MATR3)
• Gene Name: MATR3
• Related Disease:
  Adrenocortical carcinoma
  Amyotrophic lateral sclerosis type 1
  Amyotrophic lateral sclerosis type 21
  Distal myopathy
  Frontotemporal dementia
  Hepatocellular carcinoma
  HIV infectious disease
  Malignant tumor of adrenal cortex
  Muscular dystrophy
  Myopathy
  Pick disease
  Amyotrophic lateral sclerosis
  Distal myopathy with vocal cord weakness
  Neuroblastoma
  Aorta coarctation
  Myofibrillar myopathy
  Patent ductus arteriosus
  Ventricular septal defect
• UniProt ID: MATR3_HUMAN
• Sequence:
  MSKSFQQSSLSRDSQGHGRDLSAAGIGLLAAATQSLSMPASLGRMNQGTARLASLMNLGM
  SSSLNQQGAHSALSSASTSSHNLQSIFNIGSRGPLPLSSQHRGDADQASNILASFGLSAR
  DLDELSRYPEDKITPENLPQILLQLKRRRTEEGPTLSYGRDGRSATREPPYRVPRDDWEE
  KRHFRRDSFDDRGPSLNPVLDYDHGSRSQESGYYDRMDYEDDRLRDGERCRDDSFFGETS
  HNYHKFDSEYERMGRGPGPLQERSLFEKKRGAPPSSNIEDFHGLLPKGYPHLCSICDLPV
  HSNKEWSQHINGASHSRRCQLLLEIYPEWNPDNDTGHTMGDPFMLQQSTNPAPGILGPPP
  PSFHLGGPAVGPRGNLGAGNGNLQGPRHMQKGRVETSRVVHIMDFQRGKNLRYQLLQLVE
  PFGVISNHLILNKINEAFIEMATTEDAQAAVDYYTTTPALVFGKPVRVHLSQKYKRIKKP
  EGKPDQKFDQKQELGRVIHLSNLPHSGYSDSAVLKLAEPYGKIKNYILMRMKSQAFIEME
  TREDAMAMVDHCLKKALWFQGRCVKVDLSEKYKKLVLRIPNRGIDLLKKDKSRKRSYSPD
  GKESPSDKKSKTDGSQKTESSTEGKEQEEKSGEDGEKDTKDDQTEQEPNMLLESEDELLV
  DEEEAAALLESGSSVGDETDLANLGDVASDGKKEPSDKAVKKDGSASAAAKKKLKKVDKI
  EELDQENEAALENGIKNEENTEPGAESSENADDPNKDTSENADGQSDENKDDYTIPDEYR
  IGPYQPNVPVGIDYVIPKTGFYCKLCSLFYTNEEVAKNTHCSSLPHYQKLKKFLNKLAEE
  RRQKKET
• Function: May play a role in transcription or may interact with other nuclear matrix proteins to form the internal fibrogranular network. In association with the SFPQ-NONO heteromer may play a role in nuclear retention of defective RNAs. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway. Binds to N6-methyladenosine (m6A)-containing mRNAs and contributes to MYC stability by binding to m6A-containing MYC mRNAs. May bind to specific miRNA hairpins.
• KEGG Pathway: Amyotrophic lateral sclerosis (hsa05014)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adrenocortical carcinoma	DISZF4HX	Strong	Altered Expression	[1]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[2]
Amyotrophic lateral sclerosis type 21	DISJTD4Y	Strong	Autosomal dominant	[3]
Distal myopathy	DIS7F5R0	Strong	Genetic Variation	[4]
Frontotemporal dementia	DISKYHXL	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[6]
Malignant tumor of adrenal cortex	DIS7E0I8	Strong	Altered Expression	[1]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[7]
Myopathy	DISOWG27	Strong	Genetic Variation	[4]
Pick disease	DISP6X50	Strong	Biomarker	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Supportive	Autosomal dominant	[3]
Distal myopathy with vocal cord weakness	DISIA80W	Supportive	Autosomal dominant	[8]
Neuroblastoma	DISVZBI4	Disputed	Biomarker	[9]
Aorta coarctation	DISAFXDJ	Limited	Biomarker	[10]
Myofibrillar myopathy	DISF24LW	Limited	Biomarker	[8]
Patent ductus arteriosus	DIS9P8YS	Limited	Biomarker	[10]
Ventricular septal defect	DISICO41	Limited	Biomarker	[10]

16 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 Matrin-3 (MATR3).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Matrin-3 (MATR3).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Matrin-3 (MATR3).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Matrin-3 (MATR3).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Matrin-3 (MATR3).	[15]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Matrin-3 (MATR3).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Matrin-3 (MATR3).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Matrin-3 (MATR3).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Matrin-3 (MATR3).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Matrin-3 (MATR3).	[19]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Matrin-3 (MATR3).	[14]
ACYLINE	DM9GRTK	Phase 2	ACYLINE increases the expression of Matrin-3 (MATR3).	[20]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Matrin-3 (MATR3).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Matrin-3 (MATR3).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Matrin-3 (MATR3).	[18]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Matrin-3 (MATR3).	[26]

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 Matrin-3 (MATR3).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Matrin-3 (MATR3).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Matrin-3 (MATR3).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Matrin-3 (MATR3).	[23]

References

• [1] MicroRNA signature in massive macronodular adrenocortical disease and implications for adrenocortical tumourigenesis.Clin Endocrinol (Oxf). 2010 Jun;72(6):744-51. doi: 10.1111/j.1365-2265.2009.03725.x. Epub 2009 Oct 22.
• [2] The ALS-linked E102Q mutation in Sigma receptor-1 leads to ER stress-mediated defects in protein homeostasis and dysregulation of RNA-binding proteins.Cell Death Differ. 2017 Oct;24(10):1655-1671. doi: 10.1038/cdd.2017.88. Epub 2017 Jun 16.
• [3] Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci. 2014 May;17(5):664-666. doi: 10.1038/nn.3688. Epub 2014 Mar 30.
• [4] Characterization of gene regulation and protein interaction networks for Matrin 3 encoding mutations linked to amyotrophic lateral sclerosis and myopathy.Sci Rep. 2018 Mar 6;8(1):4049. doi: 10.1038/s41598-018-21371-4.
• [5] Long-Read RNA Sequencing Identifies Alternative Splice Variants in Hepatocellular Carcinoma and Tumor-Specific Isoforms.Hepatology. 2019 Sep;70(3):1011-1025. doi: 10.1002/hep.30500. Epub 2019 Mar 22.
• [6] Posttranscriptional Regulation of HIV-1 Gene Expression during Replication and Reactivation from Latency by Nuclear Matrix Protein MATR3.mBio. 2018 Nov 13;9(6):e02158-18. doi: 10.1128/mBio.02158-18.
• [7] A study of FHL1, BAG3, MATR3, PTRF and TCAP in Australian muscular dystrophy patients.Neuromuscul Disord. 2011 Nov;21(11):776-81. doi: 10.1016/j.nmd.2011.05.007. Epub 2011 Jun 17.
• [8] Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3. Am J Hum Genet. 2009 Apr;84(4):511-8. doi: 10.1016/j.ajhg.2009.03.006. Epub 2009 Apr 2.
• [9] RNA-Binding Proteomics Reveals MATR3 Interacting with lncRNA SNHG1 To Enhance Neuroblastoma Progression.J Proteome Res. 2019 Jan 4;18(1):406-416. doi: 10.1021/acs.jproteome.8b00693. Epub 2018 Dec 14.
• [10] MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus.Hum Mol Genet. 2015 Apr 15;24(8):2375-89. doi: 10.1093/hmg/ddv004. Epub 2015 Jan 7.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] 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.
• [14] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [20] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [25] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [26] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.