Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7ZNYHT)

• DOT Name: Multimerin-1 (MMRN1)
• Synonyms: EMILIN-4; Elastin microfibril interface located protein 4; Elastin microfibril interfacer 4; Endothelial cell multimerin
• Gene Name: MMRN1
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Colon cancer
  Glioma
  Obesity
  Acute coronary syndrome
  Advanced cancer
  Asthma
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Chronic kidney disease
  Chronic obstructive pulmonary disease
  Coronary atherosclerosis
  Coronary heart disease
  Diabetic kidney disease
  Glaucoma/ocular hypertension
  Hepatocellular carcinoma
  Leiomyoma
  Liver cirrhosis
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  OPTN-related open angle glaucoma
  Osteoarthritis
  Pancreatic cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Renal fibrosis
  Rheumatoid arthritis
  Stroke
  Systemic sclerosis
  Thyroid gland carcinoma
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Uterine fibroids
  Cardiovascular disease
  Glomerulosclerosis
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Primary myelofibrosis
  Prostate cancer
  Acute myocardial infarction
  Colon carcinoma
  Glioblastoma multiforme
  Matthew-Wood syndrome
  Melanoma
  Metastatic malignant neoplasm
  Parkinson disease
• UniProt ID: MMRN1_HUMAN
• Pfam ID: PF00386 ; PF00008 ; PF07546
• Sequence:
  MKGARLFVLLSSLWSGGIGLNNSKHSWTIPEDGNSQKTMPSASVPPNKIQSLQILPTTRV
  MSAEIATTPEARTSEDSLLKSTLPPSETSAPAEGVRNQTLTSTEKAEGVVKLQNLTLPTN
  ASIKFNPGAESVVLSNSTLKFLQSFARKSNEQATSLNTVGGTGGIGGVGGTGGVGNRAPR
  ETYLSRGDSSSSQRTDYQKSNFETTRGKNWCAYVHTRLSPTVILDNQVTYVPGGKGPCGW
  TGGSCPQRSQKISNPVYRMQHKIVTSLDWRCCPGYSGPKCQLRAQEQQSLIHTNQAESHT
  AVGRGVAEQQQQQGCGDPEVMQKMTDQVNYQAMKLTLLQKKIDNISLTVNDVRNTYSSLE
  GKVSEDKSREFQSLLKGLKSKSINVLIRDIVREQFKIFQNDMQETVAQLFKTVSSLSEDL
  ESTRQIIQKVNESVVSIAAQQKFVLVQENRPTLTDIVELRNHIVNVRQEMTLTCEKPIKE
  LEVKQTHLEGALEQEHSRSILYYESLNKTLSKLKEVHEQLLSTEQVSDQKNAPAAESVSN
  NVTEYMSTLHENIKKQSLMMLQMFEDLHIQESKINNLTVSLEMEKESLRGECEDMLSKCR
  NDFKFQLKDTEENLHVLNQTLAEVLFPMDNKMDKMSEQLNDLTYDMEILQPLLEQGASLR
  QTMTYEQPKEAIVIRKKIENLTSAVNSLNFIIKELTKRHNLLRNEVQGRDDALERRINEY
  ALEMEDGLNKTMTIINNAIDFIQDNYALKETLSTIKDNSEIHHKCTSDMETILTFIPQFH
  RLNDSIQTLVNDNQRYNFVLQVAKTLAGIPRDEKLNQSNFQKMYQMFNETTSQVRKYQQN
  MSHLEEKLLLTTKISKNFETRLQDIESKVTQTLIPYYISVKKGSVVTNERDQALQLQVLN
  SRFKALEAKSIHLSINFFSLNKTLHEVLTMCHNASTSVSELNATIPKWIKHSLPDIQLLQ
  KGLTEFVEPIIQIKTQAALSNLTCCIDRSLPGSLANVVKSQKQVKSLPKKINALKKPTVN
  LTTVLIGRTQRNTDNIIYPEEYSSCSRHPCQNGGTCINGRTSFTCACRHPFTGDNCTIKL
  VEENALAPDFSKGSYRYAPMVAFFASHTYGMTIPGPILFNNLDVNYGASYTPRTGKFRIP
  YLGVYVFKYTIESFSAHISGFLVVDGIDKLAFESENINSEIHCDRVLTGDALLELNYGQE
  VWLRLAKGTIPAKFPPVTTFSGYLLYRT
• Function: Carrier protein for platelet (but not plasma) factor V/Va. Plays a role in the storage and stabilization of factor V in platelets. Upon release following platelet activation, may limit platelet and plasma factor Va-dependent thrombin generation. Ligand for integrin alpha-IIb/beta-3 and integrin alpha-V/beta-3 on activated platelets, and may function as an extracellular matrix or adhesive protein.
• Tissue Specificity: Synthesized by endothelial cells and megakaryocytes. Stored in platelet alpha granules and endothelial cell Weibel-Palade bodies, following activation of these cells, it is released and attached to megakaryocytes, platelets, endothelium and subendothelium of blood vessels. Not found in plasma. Found in vascular tissues such as placenta, lung, and liver.
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Definitive	Biomarker	[1]
Atherosclerosis	DISMN9J3	Definitive	Biomarker	[1]
Colon cancer	DISVC52G	Definitive	Genetic Variation	[2]
Glioma	DIS5RPEH	Definitive	Altered Expression	[3]
Obesity	DIS47Y1K	Definitive	Biomarker	[4]
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[5]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[6]
Asthma	DISW9QNS	Strong	Biomarker	[7]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[10]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[11]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[12]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[12]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[13]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Altered Expression	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Leiomyoma	DISLDDFN	Strong	Biomarker	[16]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[17]
Lung cancer	DISCM4YA	Strong	Biomarker	[18]
Lung carcinoma	DISTR26C	Strong	Biomarker	[18]
Neoplasm	DISZKGEW	Strong	Biomarker	[19]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[20]
OPTN-related open angle glaucoma	DISDR98A	Strong	Biomarker	[21]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[22]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[23]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[24]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[25]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[26]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[6]
Stroke	DISX6UHX	Strong	Biomarker	[27]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[28]
Thyroid gland carcinoma	DISMNGZ0	Strong	Genetic Variation	[29]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[30]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[8]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[8]
Uterine fibroids	DISBZRMJ	Strong	Biomarker	[31]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[32]
Glomerulosclerosis	DISJF20Z	moderate	Altered Expression	[33]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Moderate	Autosomal recessive	[34]
Primary myelofibrosis	DIS6L0CN	moderate	Biomarker	[35]
Prostate cancer	DISF190Y	moderate	Biomarker	[24]
Acute myocardial infarction	DISE3HTG	Limited	Genetic Variation	[36]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[37]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[38]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[39]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[40]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[41]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Multimerin-1 (MMRN1).	[43]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Multimerin-1 (MMRN1).	[44]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Multimerin-1 (MMRN1).	[45]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Multimerin-1 (MMRN1).	[47]

1 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 Multimerin-1 (MMRN1).	[46]

References

• [1] A biomarker of collagen type I degradation is associated with cardiovascular events and mortality in patients with atherosclerosis.J Intern Med. 2019 Jan;285(1):118-123. doi: 10.1111/joim.12819. Epub 2018 Aug 28.
• [2] A core matrisome gene signature predicts cancer outcome.Br J Cancer. 2018 Feb 6;118(3):435-440. doi: 10.1038/bjc.2017.458. Epub 2018 Jan 23.
• [3] Tenascin-C is expressed by human glioma in vivo and shows a strong association with tumor blood vessels.Cell Tissue Res. 2013 Nov;354(2):409-30. doi: 10.1007/s00441-013-1704-9. Epub 2013 Aug 21.
• [4] Increased fibrosis: A novel means by which GH influences white adipose tissue function.Growth Horm IGF Res. 2018 Apr;39:45-53. doi: 10.1016/j.ghir.2017.12.010. Epub 2017 Dec 20.
• [5] Glycoprotein Ia C807T: Polymorphisms and Their Association with Platelet Function in Patients with the Acute Coronary Syndrome.Cardiology. 2015;132(4):213-20. doi: 10.1159/000435906. Epub 2015 Aug 15.
• [6] Citrullination of fibronectin alters integrin clustering and focal adhesion stability promoting stromal cell invasion.Matrix Biol. 2019 Sep;82:86-104. doi: 10.1016/j.matbio.2019.04.002. Epub 2019 Apr 17.
• [7] Protocatechuic acid inhibits TGF-1-induced proliferation and migration of human airway smooth muscle cells.J Pharmacol Sci. 2019 Jan;139(1):9-14. doi: 10.1016/j.jphs.2018.10.011. Epub 2018 Nov 5.
• [8] Identification of biomarkers associated with progression and prognosis in bladder cancer via co-expression analysis.Cancer Biomark. 2019;24(2):183-193. doi: 10.3233/CBM-181940.
• [9] Transcriptome profiling revealed multiple genes and ECM-receptor interaction pathways that may be associated with breast cancer.Cell Mol Biol Lett. 2019 Jun 6;24:38. doi: 10.1186/s11658-019-0162-0. eCollection 2019.
• [10] Spontaneous Extracellular Matrix Accumulation in a Human in vitro Model of Renal Fibrosis Is Mediated by V Integrins.Nephron. 2019;142(4):328-350. doi: 10.1159/000499506. Epub 2019 May 2.
• [11] The consequence of matrix dysfunction on lung immunity and the microbiome in COPD.Eur Respir Rev. 2018 Jun 27;27(148):180032. doi: 10.1183/16000617.0032-2018. Print 2018 Jun 30.
• [12] Common Variant in Glycoprotein Ia Increases Long-Term Adverse Events Risk After Coronary Artery Bypass Graft Surgery.J Am Heart Assoc. 2016 Nov 23;5(12):e004496. doi: 10.1161/JAHA.116.004496.
• [13] Bergenin impedes the generation of extracellular matrix in glomerular mesangial cells and ameliorates diabetic nephropathy in mice by inhibiting oxidative stress via the mTOR/-TrcP/Nrf2 pathway.Free Radic Biol Med. 2019 Dec;145:118-135. doi: 10.1016/j.freeradbiomed.2019.09.003. Epub 2019 Sep 5.
• [14] Activation of the NFAT-Calcium Signaling Pathway in Human Lamina Cribrosa Cells in Glaucoma.Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):831-842. doi: 10.1167/iovs.17-22531.
• [15] CXCR4-targeted liposomal mediated co-delivery of pirfenidone and AMD3100 for the treatment of TGF-induced HSC-T6 cells activation.Int J Nanomedicine. 2019 Apr 26;14:2927-2944. doi: 10.2147/IJN.S171280. eCollection 2019.
• [16] Ulipristal Acetate and Extracellular Matrix Production in Human Leiomyomas In Vivo: A Laboratory Analysis of a Randomized Placebo Controlled Trial.Reprod Sci. 2018 Feb;25(2):198-206. doi: 10.1177/1933719117728802. Epub 2017 Sep 20.
• [17] Vitronectins produced by human cirrhotic liver and CCl(4)-treated rats differ in their glycosylation pattern and tissue remodeling activity.FEBS Open Bio. 2019 Mar 18;9(4):755-768. doi: 10.1002/2211-5463.12616. eCollection 2019 Apr.
• [18] Mechanism of ECM-induced dormancy and chemoresistance in A549 human lung carcinoma cells.Oncol Rep. 2018 Apr;39(4):1765-1774. doi: 10.3892/or.2018.6258. Epub 2018 Feb 12.
• [19] Matrigel Plug Assay for In Vivo Evaluation of Angiogenesis.Methods Mol Biol. 2019;1952:219-232. doi: 10.1007/978-1-4939-9133-4_18.
• [20] p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression.Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):E10869-E10878. doi: 10.1073/pnas.1808314115. Epub 2018 Oct 31.
• [21] Identification of genes associated with primary open-angle glaucoma by bioinformatics approach.Int Ophthalmol. 2018 Feb;38(1):19-28. doi: 10.1007/s10792-017-0704-2. Epub 2017 Sep 11.
• [22] Novel nano-microspheres containing chitosan, hyaluronic acid, and chondroitin sulfate deliver growth and differentiation factor-5 plasmid for osteoarthritis gene therapy.J Zhejiang Univ Sci B. 2018 Dec.;19(12):910-923. doi: 10.1631/jzus.B1800095.
• [23] Typing of pancreatic cancer-associated fibroblasts identifies different subpopulations.World J Gastroenterol. 2018 Nov 7;24(41):4663-4678. doi: 10.3748/wjg.v24.i41.4663.
• [24] Abituzumab Targeting of V-Class Integrins Inhibits Prostate Cancer Progression.Mol Cancer Res. 2017 Jul;15(7):875-883. doi: 10.1158/1541-7786.MCR-16-0447. Epub 2017 Mar 17.
• [25] Developmental pathways in the pathogenesis of lung fibrosis.Mol Aspects Med. 2019 Feb;65:56-69. doi: 10.1016/j.mam.2018.08.004. Epub 2018 Aug 23.
• [26] Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold.J Histochem Cytochem. 2019 Sep;67(9):643-661. doi: 10.1369/0022155419849388. Epub 2019 May 22.
• [27] Changes in resting-state functional connectivity after stroke in a mouse brain lacking extracellular matrix components.Neurobiol Dis. 2018 Apr;112:91-105. doi: 10.1016/j.nbd.2018.01.011. Epub 2018 Jan 31.
• [28] Effects of selexipag and its active metabolite in contrasting the profibrotic myofibroblast activity in cultured scleroderma skin fibroblasts.Arthritis Res Ther. 2018 May 2;20(1):77. doi: 10.1186/s13075-018-1577-0.
• [29] Vitamin D receptor expression is linked to potential markers of human thyroid papillary carcinoma.J Steroid Biochem Mol Biol. 2016 May;159:26-30. doi: 10.1016/j.jsbmb.2016.02.016. Epub 2016 Feb 22.
• [30] ANRIL regulates production of extracellular matrix proteins and vasoactive factors in diabetic complications.Am J Physiol Endocrinol Metab. 2018 Mar 1;314(3):E191-E200. doi: 10.1152/ajpendo.00268.2017. Epub 2017 Nov 7.
• [31] Natural Antioxidant Resveratrol Suppresses Uterine Fibroid Cell Growth and Extracellular Matrix Formation In Vitro and In Vivo.Antioxidants (Basel). 2019 Apr 12;8(4):99. doi: 10.3390/antiox8040099.
• [32] Anti-fibrotic effects of curcumin and some of its analogues in the heart.Heart Fail Rev. 2020 Sep;25(5):731-743. doi: 10.1007/s10741-019-09854-6.
• [33] Triptolide prevents extracellular matrix accumulation in experimental diabetic kidney disease by targeting microRNA-137/Notch1 pathway.J Cell Physiol. 2018 Mar;233(3):2225-2237. doi: 10.1002/jcp.26092. Epub 2017 Sep 13.
• [34] A genomics approach to male infertility. Genet Med. 2020 Dec;22(12):1967-1975. doi: 10.1038/s41436-020-0916-0. Epub 2020 Jul 28.
• [35] The role of the extracellular matrix in primary myelofibrosis.Blood Cancer J. 2017 Feb 3;7(2):e525. doi: 10.1038/bcj.2017.6.
• [36] Polymorphisms of genes affecting thrombosis and risk of myocardial infarction.Eur J Clin Invest. 2002 Sep;32(9):643-8. doi: 10.1046/j.1365-2362.2002.01047.x.
• [37] Colon cancer recurrenceassociated genes revealed by WGCNA coexpression network analysis.Mol Med Rep. 2017 Nov;16(5):6499-6505. doi: 10.3892/mmr.2017.7412. Epub 2017 Aug 31.
• [38] Development of a Function-Blocking Antibody Against Fibulin-3 as a Targeted Reagent for Glioblastoma.Clin Cancer Res. 2018 Feb 15;24(4):821-833. doi: 10.1158/1078-0432.CCR-17-1628. Epub 2017 Nov 16.
• [39] Targeting Pancreatic Stellate Cells in Cancer.Trends Cancer. 2019 Feb;5(2):128-142. doi: 10.1016/j.trecan.2019.01.001. Epub 2019 Feb 1.
• [40] MMP7 sensitivity of mutant ECM proteins: An indicator of melanoma survival rates and T-cell infiltration.Clin Biochem. 2019 Jan;63:85-91. doi: 10.1016/j.clinbiochem.2018.11.004. Epub 2018 Nov 8.
• [41] Identification of key candidate genes involved in melanoma metastasis.Mol Med Rep. 2019 Aug;20(2):903-914. doi: 10.3892/mmr.2019.10314. Epub 2019 May 30.
• [42] Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database.PLoS Genet. 2012;8(3):e1002548. doi: 10.1371/journal.pgen.1002548. Epub 2012 Mar 15.
• [43] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [44] 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.
• [45] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [46] 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.
• [47] 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.