Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM0XU0U)

• DOT Name: Multiple coagulation factor deficiency protein 2 (MCFD2)
• Synonyms: Neural stem cell-derived neuronal survival protein
• Gene Name: MCFD2
• Related Disease:
  Factor 5 and Factor VIII, combined deficiency of, 2
  Advanced cancer
  Coagulation defect
  Congenital dyserythropoietic anemia type 2
  Factor V and factor VIII, combined deficiency of, type 1
  Haemophilia A
  Hematologic disease
  Seminoma
  Vitamin K-dependent clotting factors, combined deficiency of, type 1
  Combined deficiency of factor V and factor VIII
  Coronary atherosclerosis
  Coronary heart disease
• UniProt ID: MCFD2_HUMAN
• PDB ID: 2VRG; 3A4U; 3LCP; 3WHT; 3WHU; 3WNX; 4YGB; 4YGC; 4YGD; 4YGE
• Pfam ID: PF13499
• Sequence:
  MTMRSLLRTPFLCGLLWAFCAPGARAEEPAASFSQPGSMGLDKNTVHDQEHIMEHLEGVI
  NKPEAEMSPQELQLHYFKMHDYDGNNLLDGLELSTAITHVHKEEGSEQAPLMSEDELINI
  IDGVLRDDDKNNDGYIDYAEFAKSLQ
• Function: The MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins. Plays a role in the secretion of coagulation factors.
• Reactome Pathway:
  Cargo concentration in the ER (R-HSA-5694530)
  Transport to the Golgi and subsequent modification (R-HSA-948021)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Factor 5 and Factor VIII, combined deficiency of, 2	DIS40TZ9	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Coagulation defect	DIS9X3H6	Strong	Genetic Variation	[3]
Congenital dyserythropoietic anemia type 2	DIS5RDUE	Strong	Genetic Variation	[4]
Factor V and factor VIII, combined deficiency of, type 1	DIS1K6SD	Strong	Genetic Variation	[5]
Haemophilia A	DIS0RQ2E	Strong	Genetic Variation	[6]
Hematologic disease	DIS9XD9A	Strong	Biomarker	[2]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[7]
Vitamin K-dependent clotting factors, combined deficiency of, type 1	DIS1X7PX	Strong	Biomarker	[8]
Combined deficiency of factor V and factor VIII	DISZM9BG	Supportive	Autosomal recessive	[9]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[10]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[10]

12 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 Multiple coagulation factor deficiency protein 2 (MCFD2).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[17]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[18]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Multiple coagulation factor deficiency protein 2 (MCFD2).	[23]

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 Multiple coagulation factor deficiency protein 2 (MCFD2).	[21]

References

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• [2] Multiple coagulation factor deficiency protein 2 as a crucial component in metastasis of human oral cancer.Exp Cell Res. 2018 Jul 1;368(1):119-125. doi: 10.1016/j.yexcr.2018.04.021. Epub 2018 Apr 19.
• [3] Combined deficiency of coagulation factors V and VIII: an update.Semin Thromb Hemost. 2013 Sep;39(6):613-20. doi: 10.1055/s-0033-1349223. Epub 2013 Jul 12.
• [4] The COPII pathway and hematologic disease.Blood. 2012 Jul 5;120(1):31-8. doi: 10.1182/blood-2012-01-292086. Epub 2012 May 14.
• [5] Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.Blood. 2019 Dec 5;134(23):2082-2091. doi: 10.1182/blood.2018891192.
• [6] The first case of combined coagulation factor V and coagulation factor VIII deficiency in Poland due to a novel p.Tyr135Asn missense mutation in the MCFD2 gene.Blood Coagul Fibrinolysis. 2008 Sep;19(6):531-534. doi: 10.1097/MBC.0b013e3283061103.
• [7] Novel germ cell markers characterize testicular seminoma and fetal testis.Mol Hum Reprod. 2007 Oct;13(10):721-7. doi: 10.1093/molehr/gam059. Epub 2007 Sep 4.
• [8] Familial multiple coagulation factor deficiencies: new biologic insight from rare genetic bleeding disorders.J Thromb Haemost. 2004 Sep;2(9):1564-72. doi: 10.1111/j.1538-7836.2004.00857.x.
• [9] Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. Nat Genet. 2003 Jun;34(2):220-5. doi: 10.1038/ng1153.
• [10] Successful percutaneous coronary intervention in a patient with combined deficiency of FV and FVIII due to novel compound heterozygous mutations in LMAN1.Haemophilia. 2013 Jul;19(4):607-10. doi: 10.1111/hae.12128. Epub 2013 Apr 5.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [20] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [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] 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.
• [23] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.