Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYT3TT5)

• DOT Name: Microcephalin (MCPH1)
• Gene Name: MCPH1
• Related Disease:
  Astrocytoma
  Lung cancer
  Lung carcinoma
  Malaria
  Malignant glioma
  Microcephaly 1, primary, autosomal recessive
  Microcephaly with intellectual disability
  Advanced cancer
  Autism
  Autism spectrum disorder
  B-cell neoplasm
  Bipolar disorder
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Colorectal carcinoma
  Depression
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  High blood pressure
  Kidney cancer
  Mantle cell lymphoma
  Mental disorder
  Multiple endocrine neoplasia type 2A
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Ovarian cancer
  Pancreatic cancer
  Pancreatic tumour
  Parkinson disease
  Renal carcinoma
  Renal cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Neoplasm
  Neuroblastoma
  Small lymphocytic lymphoma
  Squamous cell carcinoma
  Autosomal recessive primary microcephaly
  Psychotic disorder
  Acute otitis media
  Chromosomal disorder
  Hereditary breast carcinoma
  Leukopenia
  Otitis media
  Ovarian neoplasm
  Schizophrenia
  Familial ovarian cancer
• UniProt ID: MCPH1_HUMAN
• PDB ID: 2WT8; 3KTF; 3PA6; 3SHT; 3SHV; 3SZM; 3T1N; 3U3Z; 7C5D
• Pfam ID: PF12258 ; PF12738
• Sequence:
  MAAPILKDVVAYVEVWSSNGTENYSKTFTTQLVDMGAKVSKTFNKQVTHVIFKDGYQSTW
  DKAQKRGVKLVSVLWVEKCRTAGAHIDESLFPAANMNEHLSSLIKKKRKCMQPKDFNFKT
  PENDKRFQKKFEKMAKELQRQKTNLDDDVPILLFESNGSLIYTPTIEINSRHHSAMEKRL
  QEMKEKRENLSPTSSQMIQQSHDNPSNSLCEAPLNISRDTLCSDEYFAGGLHSSFDDLCG
  NSGCGNQERKLEGSINDIKSDVCISSLVLKANNIHSSPSFTHLDKSSPQKFLSNLSKEEI
  NLQRNIAGKVVTPDQKQAAGMSQETFEEKYRLSPTLSSTKGHLLIHSRPRSSSVKRKRVS
  HGSHSPPKEKCKRKRSTRRSIMPRLQLCRSEDRLQHVAGPALEALSCGESSYDDYFSPDN
  LKERYSENLPPESQLPSSPAQLSCRSLSKKERTSIFEMSDFSCVGKKTRTVDITNFTAKT
  ISSPRKTGNGEGRATSSCVTSAPEEALRCCRQAGKEDACPEGNGFSYTIEDPALPKGHDD
  DLTPLEGSLEEMKEAVGLKSTQNKGTTSKISNSSEGEAQSEHEPCFIVDCNMETSTEEKE
  NLPGGYSGSVKNRPTRHDVLDDSCDGFKDLIKPHEELKKSGRGKKPTRTLVMTSMPSEKQ
  NVVIQVVDKLKGFSIAPDVCETTTHVLSGKPLRTLNVLLGIARGCWVLSYDWVLWSLELG
  HWISEEPFELSHHFPAAPLCRSECHLSAGPYRGTLFADQPAMFVSPASSPPVAKLCELVH
  LCGGRVSQVPRQASIVIGPYSGKKKATVKYLSEKWVLDSITQHKVCAPENYLLSQ
• Function: Implicated in chromosome condensation and DNA damage induced cellular responses. May play a role in neurogenesis and regulation of the size of the cerebral cortex.
• Tissue Specificity: Expressed in fetal brain, liver and kidney.
• Reactome Pathway: Condensation of Prophase Chromosomes (R-HSA-2299718)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Astrocytoma	DISL3V18	Definitive	Altered Expression	[1]
Lung cancer	DISCM4YA	Definitive	Biomarker	[2]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[2]
Malaria	DISQ9Y50	Definitive	Biomarker	[3]
Malignant glioma	DISFXKOV	Definitive	Biomarker	[1]
Microcephaly 1, primary, autosomal recessive	DISBKRMO	Definitive	Autosomal recessive	[4]
Microcephaly with intellectual disability	DISSR6LP	Definitive	Autosomal recessive	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Autism	DISV4V1Z	Strong	Biomarker	[7]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[8]
B-cell neoplasm	DISVY326	Strong	Biomarker	[9]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[10]
Bladder cancer	DISUHNM0	Strong	Biomarker	[11]
Breast cancer	DIS7DPX1	Strong	Biomarker	[12]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[12]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[13]
Carcinoma	DISH9F1N	Strong	Altered Expression	[14]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[15]
Depression	DIS3XJ69	Strong	Biomarker	[16]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[17]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[18]
High blood pressure	DISY2OHH	Strong	Biomarker	[19]
Kidney cancer	DISBIPKM	Strong	Altered Expression	[20]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[21]
Mental disorder	DIS3J5R8	Strong	Biomarker	[22]
Multiple endocrine neoplasia type 2A	DIS7D3W2	Strong	Biomarker	[23]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[24]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[25]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[26]
Pancreatic cancer	DISJC981	Strong	Biomarker	[27]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[27]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[28]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[20]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[20]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[11]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	moderate	Altered Expression	[13]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[29]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[30]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[26]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[31]
Psychotic disorder	DIS4UQOT	Disputed	Genetic Variation	[32]
Acute otitis media	DISL8D8G	Limited	Biomarker	[33]
Chromosomal disorder	DISM5BB5	Limited	Biomarker	[34]
Hereditary breast carcinoma	DISAEZT5	Limited	Autosomal dominant	[5]
Leukopenia	DISJMBMM	Limited	Genetic Variation	[35]
Otitis media	DISGZDUO	Limited	Biomarker	[33]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[36]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[32]
Familial ovarian cancer	DISGLR2C	No Known	Autosomal dominant	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Epirubicin	DMPDW6T	Approved	Microcephalin (MCPH1) increases the Leukopenia ADR of Epirubicin.	[35]

13 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 Microcephalin (MCPH1).	[37]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Microcephalin (MCPH1).	[38]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Microcephalin (MCPH1).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Microcephalin (MCPH1).	[40]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Microcephalin (MCPH1).	[41]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Microcephalin (MCPH1).	[43]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Microcephalin (MCPH1).	[44]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Microcephalin (MCPH1).	[45]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Microcephalin (MCPH1).	[46]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Microcephalin (MCPH1).	[47]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Microcephalin (MCPH1).	[48]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Microcephalin (MCPH1).	[52]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Microcephalin (MCPH1).	[53]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Microcephalin (MCPH1).	[42]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Microcephalin (MCPH1).	[49]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Microcephalin (MCPH1).	[50]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Microcephalin (MCPH1).	[51]

References

• [1] Expression analysis of the autosomal recessive primary microcephaly genes MCPH1 (microcephalin) and MCPH5 (ASPM, abnormal spindle-like, microcephaly associated) in human malignant gliomas.Oncol Rep. 2008 Aug;20(2):301-8.
• [2] Overexpression of MCPH1 inhibits the migration and invasion of lung cancer cells.Onco Targets Ther. 2018 May 25;11:3111-3117. doi: 10.2147/OTT.S156102. eCollection 2018.
• [3] Microcrystalline Tyrosine (MCT()): A Depot Adjuvant in Licensed Allergy Immunotherapy Offers New Opportunities in Malaria.Vaccines (Basel). 2017 Sep 27;5(4):32. doi: 10.3390/vaccines5040032.
• [4] A clinical and molecular genetic study of 112 Iranian families with primary microcephaly. J Med Genet. 2010 Dec;47(12):823-8. doi: 10.1136/jmg.2009.076398. Epub 2010 Oct 26.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [6] Cellular Uptake of MCT1 Inhibitors AR-C155858 and AZD3965 and Their Effects on MCT-Mediated Transport of L-Lactate in Murine 4T1 Breast Tumor Cancer Cells.AAPS J. 2019 Jan 7;21(2):13. doi: 10.1208/s12248-018-0279-5.
• [7] Transmitted duplication of 8p23.1-8p23.2 associated with speech delay, autism and learning difficulties.Eur J Hum Genet. 2009 Jan;17(1):37-43. doi: 10.1038/ejhg.2008.133. Epub 2008 Aug 20.
• [8] Social Responsiveness Scale-aided analysis of the clinical impact of copy number variations in autism.Neurogenetics. 2011 Nov;12(4):315-23. doi: 10.1007/s10048-011-0297-2. Epub 2011 Aug 12.
• [9] BRCT-domain protein BRIT1 influences class switch recombination.Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8354-8359. doi: 10.1073/pnas.1708211114. Epub 2017 Jul 19.
• [10] The genome in three dimensions: a new frontier in human brain research.Biol Psychiatry. 2014 Jun 15;75(12):961-9. doi: 10.1016/j.biopsych.2013.07.015. Epub 2013 Aug 16.
• [11] CD147 and MCT1-potential partners in bladder cancer aggressiveness and cisplatin resistance.Mol Carcinog. 2015 Nov;54(11):1451-66. doi: 10.1002/mc.22222. Epub 2014 Sep 27.
• [12] Feasibility, Safety, and Beneficial Effects of MCT-Based Ketogenic Diet for Breast Cancer Treatment: A Randomized Controlled Trial Study.Nutr Cancer. 2020;72(4):627-634. doi: 10.1080/01635581.2019.1650942. Epub 2019 Sep 9.
• [13] Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly.Int J Cancer. 2019 Oct 15;145(8):2070-2081. doi: 10.1002/ijc.32234. Epub 2019 Mar 21.
• [14] Deregulation of microcephalin and ASPM expression are correlated with epithelial ovarian cancer progression.PLoS One. 2014 May 15;9(5):e97059. doi: 10.1371/journal.pone.0097059. eCollection 2014.
• [15] Polymorphisms of monocarboxylate transporter genes are associated with clinical outcomes in patients with colorectal cancer.J Cancer Res Clin Oncol. 2015 Jun;141(6):1095-102. doi: 10.1007/s00432-014-1877-y. Epub 2014 Dec 10.
• [16] Cognitive and Metacognitive Mechanisms of Change in Metacognitive Training for Depression.Sci Rep. 2017 Jun 14;7(1):3449. doi: 10.1038/s41598-017-03626-8.
• [17] Expression analysis of the MCPH1/BRIT1 and BRCA1 tumor suppressor genes and telomerase splice variants in epithelial ovarian cancer.Gene. 2018 Sep 25;672:34-44. doi: 10.1016/j.gene.2018.05.113. Epub 2018 May 31.
• [18] Multicarotenoids at Physiological Levels Inhibit Metastasis in Human Hepatocarcinoma SK-Hep-1 Cells.Nutr Cancer. 2015;67(4):676-86. doi: 10.1080/01635581.2015.1019633. Epub 2015 Apr 14.
• [19] Involvement of S100A4/Mts1 and associated proteins in the protective effect of fluoxetine against MCT - Induced pulmonary hypertension in rats.J Chin Med Assoc. 2018 Dec;81(12):1077-1087. doi: 10.1016/j.jcma.2018.03.013. Epub 2018 Jul 19.
• [20] Primary microcephaly gene MCPH1 shows a novel molecular biomarker of human renal carcinoma and is regulated by miR-27a.Int J Clin Exp Pathol. 2014 Jul 15;7(8):4895-903. eCollection 2014.
• [21] Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling.Blood. 2010 Aug 12;116(6):953-61. doi: 10.1182/blood-2010-01-263806. Epub 2010 Apr 26.
• [22] Sex-dependent association of common variants of microcephaly genes with brain structure.Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):384-8. doi: 10.1073/pnas.0908454107. Epub 2009 Dec 22.
• [23] Plasma and tumor dopamine-beta-hydroxylase activity in patients with familial pheochromocytomas.Metabolism. 1978 Dec;27(12):1797-802. doi: 10.1016/0026-0495(78)90266-4.
• [24] The E3 ubiquitin ligase APC/C(C)(dh1) degrades MCPH1 after MCPH1-TrCP2-Cdc25A-mediated mitotic entry to ensure neurogenesis.EMBO J. 2017 Dec 15;36(24):3666-3681. doi: 10.15252/embj.201694443. Epub 2017 Nov 17.
• [25] Genetic variations in monocarboxylate transporter genes as predictors of clinical outcomes in non-small cell lung cancer.Tumour Biol. 2015 May;36(5):3931-9. doi: 10.1007/s13277-014-3036-0. Epub 2015 Jan 13.
• [26] Primary microcephaly gene MCPH1 shows signatures of tumor suppressors and is regulated by miR-27a in oral squamous cell carcinoma.PLoS One. 2013;8(3):e54643. doi: 10.1371/journal.pone.0054643. Epub 2013 Mar 5.
• [27] Mast Cell Tryptase Contributes to Pancreatic Cancer Growth through Promoting Angiogenesis via Activation of Angiopoietin-1.Int J Mol Sci. 2016 May 27;17(6):834. doi: 10.3390/ijms17060834.
• [28] Dynamics of Parkinson's Disease Multimodal Complex Treatment in Germany from 2010?016: Patient Characteristics, Access to Treatment, and Formation of Regional Centers.Cells. 2019 Feb 11;8(2):151. doi: 10.3390/cells8020151.
• [29] The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma.Mol Pharmacol. 2006 Dec;70(6):2108-15. doi: 10.1124/mol.106.026245. Epub 2006 Sep 25.
• [30] MCPH1 maintains long-term epigenetic silencing of ANGPT2 in chronic lymphocytic leukemia.FEBS J. 2015 May;282(10):1939-52. doi: 10.1111/febs.13245. Epub 2015 Mar 9.
• [31] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [32] Genetic association and functional characterization of MCPH1 gene variation in bipolar disorder and schizophrenia.Am J Med Genet B Neuropsychiatr Genet. 2019 Jun;180(4):258-265. doi: 10.1002/ajmg.b.32722. Epub 2019 Mar 11.
• [33] Emerging roles of MCPH1: expedition from primary microcephaly to cancer.Eur J Cell Biol. 2014 Mar;93(3):98-105. doi: 10.1016/j.ejcb.2014.01.005. Epub 2014 Jan 29.
• [34] BRIT1/MCPH1: a guardian of genome and an enemy of tumors.Cell Cycle. 2006 Nov;5(22):2579-83. doi: 10.4161/cc.5.22.3471. Epub 2006 Nov 15.
• [35] Genome-wide association study of epirubicin-induced leukopenia in Japanese patients. Pharmacogenet Genomics. 2011 Sep;21(9):552-8. doi: 10.1097/FPC.0b013e328348e48f.
• [36] ASPM and microcephalin expression in epithelial ovarian cancer correlates with tumour grade and survival.Br J Cancer. 2011 May 10;104(10):1602-10. doi: 10.1038/bjc.2011.117. Epub 2011 Apr 19.
• [37] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [38] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [39] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [40] 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.
• [41] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [42] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [43] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [44] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [45] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [46] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [47] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [48] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [49] 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.
• [50] 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.
• [51] 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.
• [52] 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.
• [53] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [54] Genome-wide association study of epirubicin-induced leukopenia in Japanese patients. Pharmacogenet Genomics. 2011 Sep;21(9):552-8. doi: 10.1097/FPC.0b013e328348e48f.