Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5W64QY)

• DOT Name: Microfibril-associated glycoprotein 4 (MFAP4)
• Gene Name: MFAP4
• Related Disease:
  Atrial fibrillation
  Cardiac valvular dysplasia, X-linked
  Cardiovascular disease
  Hailey-Hailey disease
  Smith-Magenis syndrome
  Advanced cancer
  Arthropathy
  Chronic obstructive pulmonary disease
  Osteoarthritis
  Peripheral arterial disease
  Rheumatoid arthritis
  Synovitis
  Abdominal aortic aneurysm
  Breast cancer
  Breast carcinoma
  Diabetic neuropathy
  Marfan syndrome
  Type-1 diabetes
• UniProt ID: MFAP4_HUMAN
• PDB ID: 7ZMK
• Pfam ID: PF00147
• Sequence:
  MKALLALPLLLLLSTPPCAPQVSGIRGDALERFCLQQPLDCDDIYAQGYQSDGVYLIYPS
  GPSVPVPVFCDMTTEGGKWTVFQKRFNGSVSFFRGWNDYKLGFGRADGEYWLGLQNMHLL
  TLKQKYELRVDLEDFENNTAYAKYADFSISPNAVSAEEDGYTLFVAGFEDGGAGDSLSYH
  SGQKFSTFDRDQDLFVQNCAALSSGAFWFRSCHFANLNGFYLGGSHLSYANGINWAQWKG
  FYYSLKRTEMKIRRA
• Function: Could be involved in calcium-dependent cell adhesion or intercellular interactions. May contribute to the elastic fiber assembly and/or maintenance.
• Reactome Pathway: Molecules associated with elastic fibres (R-HSA-2129379)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[1]
Cardiac valvular dysplasia, X-linked	DISN2WU4	Strong	Altered Expression	[2]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[2]
Hailey-Hailey disease	DISCM9SG	Strong	Biomarker	[3]
Smith-Magenis syndrome	DISG4G6X	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Arthropathy	DISVEERK	moderate	Biomarker	[6]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[7]
Osteoarthritis	DIS05URM	moderate	Biomarker	[6]
Peripheral arterial disease	DIS78WFB	moderate	Biomarker	[8]
Rheumatoid arthritis	DISTSB4J	moderate	Biomarker	[9]
Synovitis	DISW2GPY	moderate	Biomarker	[9]
Abdominal aortic aneurysm	DISD06OF	Limited	Biomarker	[10]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[11]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[11]
Diabetic neuropathy	DISX6VF8	Limited	Biomarker	[12]
Marfan syndrome	DISVEUWZ	Limited	Altered Expression	[13]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[12]

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 Microfibril-associated glycoprotein 4 (MFAP4).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[20]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[22]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[23]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[26]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[29]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Microfibril-associated glycoprotein 4 (MFAP4).	[30]

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 decreases the methylation of Microfibril-associated glycoprotein 4 (MFAP4).	[25]

References

• [1] Increased plasma microfibrillar-associated protein 4 is associated with atrial fibrillation and more advanced left atrial remodelling.Arch Med Sci. 2019 May;15(3):632-640. doi: 10.5114/aoms.2018.74953. Epub 2018 Apr 6.
• [2] Localization of microfibrillar-associated protein 4 (MFAP4) in human tissues: clinical evaluation of serum MFAP4 and its association with various cardiovascular conditions.PLoS One. 2013 Dec 13;8(12):e82243. doi: 10.1371/journal.pone.0082243. eCollection 2013.
• [3] Altered levels of focal adhesion and extracellular matrix-receptor interacting proteins were identified in Hailey-Hailey disease by quantitative iTRAQ proteome analysis.J Cell Biochem. 2019 Mar;120(3):3801-3812. doi: 10.1002/jcb.27662. Epub 2018 Dec 3.
• [4] The gene for a human microfibril-associated glycoprotein is commonly deleted in Smith-Magenis syndrome patients.Hum Mol Genet. 1995 Apr;4(4):589-97. doi: 10.1093/hmg/4.4.589.
• [5] Proteomics analysis of malignant and benign prostate tissue by 2D DIGE/MS reveals new insights into proteins involved in prostate cancer.Prostate. 2015 Oct;75(14):1586-600. doi: 10.1002/pros.23034. Epub 2015 Jun 12.
• [6] Site-specific absence of microfibrillar-associated protein 4 (MFAP4) from the internal elastic membrane of arterioles in the rheumatoid arthritis synovial membrane: an immunohistochemical study in patients with advanced rheumatoid arthritis versus osteoarthritis.APMIS. 2019 Aug;127(8):588-593. doi: 10.1111/apm.12974.
• [7] A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD.Thorax. 2015 Jan;70(1):21-32. doi: 10.1136/thoraxjnl-2014-205091. Epub 2014 Jul 2.
• [8] Microfibrillar-associated protein 4 variation in symptomatic peripheral artery disease.J Transl Med. 2018 Jun 8;16(1):159. doi: 10.1186/s12967-018-1523-6.
• [9] Increased serum levels of microfibrillar-associated protein 4 (MFAP4) are not associated with clinical synovitis in rheumatoid arthritis but may reflect underlying cardiovascular comorbidity.Clin Exp Rheumatol. 2020 Jan-Feb;38(1):122-128. Epub 2019 Aug 27.
• [10] High plasma microfibrillar-associated protein 4 is associated with reduced surgical repair in abdominal aortic aneurysms.J Vasc Surg. 2020 Jun;71(6):1921-1929. doi: 10.1016/j.jvs.2019.08.253. Epub 2019 Nov 26.
• [11] Integrated analysis of microfibrillar-associated proteins reveals MFAP4 as a novel biomarker in human cancers.Epigenomics. 2019 Jan;11(1):1635-1651. doi: 10.2217/epi-2018-0080. Epub 2018 Aug 9.
• [12] Association between microfibrillar-associated protein 4 (MFAP4) and micro- and macrovascular complications in long-term type 1 diabetes mellitus.Acta Diabetol. 2017 Apr;54(4):367-372. doi: 10.1007/s00592-016-0953-y. Epub 2016 Dec 30.
• [13] Glycoproteomic Analysis of the Aortic Extracellular Matrix in Marfan Patients.Arterioscler Thromb Vasc Biol. 2019 Sep;39(9):1859-1873. doi: 10.1161/ATVBAHA.118.312175. Epub 2019 Jul 18.
• [14] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [15] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [16] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] 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.
• [19] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [20] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [21] 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.
• [22] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [23] 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.
• [24] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [25] 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.
• [26] 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.
• [27] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [28] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [29] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [30] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.