Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS5CTHX)

• DOT Name: Max dimerization protein 1 (MXD1)
• Synonyms: Max dimerizer 1; Protein MAD
• Gene Name: MXD1
• Related Disease:
  Acute myelogenous leukaemia
  Allergic contact dermatitis
  Hepatocellular carcinoma
  Myelodysplastic syndrome
  Non-insulin dependent diabetes
  Type-1 diabetes
  Type-1/2 diabetes
  Acute leukaemia
  Adult glioblastoma
  Advanced cancer
  Astrocytoma
  Attention deficit hyperactivity disorder
  B-cell lymphoma
  Bipolar disorder
  Bladder cancer
  Carcinoma of liver and intrahepatic biliary tract
  Classic Hodgkin lymphoma
  Colon cancer
  Colon carcinoma
  Depression
  Familial adenomatous polyposis
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatitis C virus infection
  Immunodeficiency
  Liver cancer
  Lung cancer
  Lung carcinoma
  Medulloblastoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Small lymphocytic lymphoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma
  Renal cell carcinoma
  Adenocarcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Esophageal cancer
  Melanoma
  Neuroblastoma
• UniProt ID: MAD1_HUMAN
• PDB ID: 1E91; 1G1E; 1NLW; 1PD7; 1S5Q
• Pfam ID: PF00010
• Sequence:
  MAAAVRMNIQMLLEAADYLERREREAEHGYASMLPYNNKDRDALKRRNKSKKNNSSSRST
  HNEMEKNRRAHLRLCLEKLKGLVPLGPESSRHTTLSLLTKAKLHIKKLEDCDRKAVHQID
  QLQREQRHLKRQLEKLGIERIRMDSIGSTVSSERSDSDREEIDVDVESTDYLTGDLDWSS
  SSVSDSDERGSMQSLGSDEGYSSTSIKRIKLQDSHKACLGL
• Function: Component of a transcriptional repressor complex together with MAX. In complex with MAX binds to the core DNA sequence 5'-CAC[GA]TG-3'. Antagonizes MYC transcriptional activity by competing with MYC for MAX binding. Binds to the TERT promoter and represses telomerase expression, possibly by interfering with MYC binding.

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Allergic contact dermatitis	DISFFVF9	Definitive	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[3]
Myelodysplastic syndrome	DISYHNUI	Definitive	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[4]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	Definitive	Altered Expression	[4]
Acute leukaemia	DISDQFDI	Strong	Biomarker	[5]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[7]
Astrocytoma	DISL3V18	Strong	Biomarker	[8]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[9]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[10]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[11]
Bladder cancer	DISUHNM0	Strong	Biomarker	[12]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[13]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Genetic Variation	[14]
Colon cancer	DISVC52G	Strong	Altered Expression	[15]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[15]
Depression	DIS3XJ69	Strong	Genetic Variation	[16]
Familial adenomatous polyposis	DISW53RE	Strong	Altered Expression	[17]
Gastric cancer	DISXGOUK	Strong	Biomarker	[18]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[19]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[20]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[21]
Liver cancer	DISDE4BI	Strong	Biomarker	[13]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[22]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[22]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[23]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[24]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[24]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[14]
Stomach cancer	DISKIJSX	Strong	Biomarker	[18]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[12]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[12]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[7]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[7]
Carcinoma	DISH9F1N	moderate	Biomarker	[25]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[25]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[26]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[27]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[28]
Esophageal cancer	DISGB2VN	Limited	Biomarker	[26]
Melanoma	DIS1RRCY	Limited	Biomarker	[29]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[30]

32 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 Max dimerization protein 1 (MXD1).	[31]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Max dimerization protein 1 (MXD1).	[32]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Max dimerization protein 1 (MXD1).	[33]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Max dimerization protein 1 (MXD1).	[34]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Max dimerization protein 1 (MXD1).	[35]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Max dimerization protein 1 (MXD1).	[36]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Max dimerization protein 1 (MXD1).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Max dimerization protein 1 (MXD1).	[38]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Max dimerization protein 1 (MXD1).	[39]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Max dimerization protein 1 (MXD1).	[40]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Max dimerization protein 1 (MXD1).	[41]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Max dimerization protein 1 (MXD1).	[42]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Max dimerization protein 1 (MXD1).	[43]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Max dimerization protein 1 (MXD1).	[44]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Max dimerization protein 1 (MXD1).	[45]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Max dimerization protein 1 (MXD1).	[41]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Max dimerization protein 1 (MXD1).	[46]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Max dimerization protein 1 (MXD1).	[47]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Max dimerization protein 1 (MXD1).	[48]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Max dimerization protein 1 (MXD1).	[49]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Max dimerization protein 1 (MXD1).	[50]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Max dimerization protein 1 (MXD1).	[51]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Max dimerization protein 1 (MXD1).	[52]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Max dimerization protein 1 (MXD1).	[53]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Max dimerization protein 1 (MXD1).	[54]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Max dimerization protein 1 (MXD1).	[55]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Max dimerization protein 1 (MXD1).	[46]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Max dimerization protein 1 (MXD1).	[56]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Max dimerization protein 1 (MXD1).	[57]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Max dimerization protein 1 (MXD1).	[58]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Max dimerization protein 1 (MXD1).	[59]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde increases the expression of Max dimerization protein 1 (MXD1).	[60]

References

• [1] Telomere length, c-myc and mad-1 expression could represent prognosis markers of myelodysplastic syndrome.Leuk Res. 2013 Nov;37(11):1538-44. doi: 10.1016/j.leukres.2013.07.022. Epub 2013 Oct 3.
• [2] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [3] Proline-rich acidic protein 1 (PRAP1) is a novel interacting partner of MAD1 and has a suppressive role in mitotic checkpoint signalling in hepatocellular carcinoma.J Pathol. 2014 May;233(1):51-60. doi: 10.1002/path.4319. Epub 2014 Jan 27.
• [4] SELF BLOOD GLUCOSE MONITORING UNDERESTIMATES HYPERGLYCEMIA AND HYPOGLYCEMIA AS COMPARED TO CONTINUOUS GLUCOSE MONITORING IN TYPE 1 AND TYPE 2 DIABETES.Endocr Pract. 2018 Jan;24(1):47-52. doi: 10.4158/EP-2017-0032. Epub 2017 Nov 16.
• [5] Expression and mutation analysis of genes that encode the Myc antagonists Mad1, Mxi1 and Rox in acute leukaemia.Leuk Lymphoma. 2007 Jun;48(6):1200-7. doi: 10.1080/10428190701342018.
• [6] MAX and MYC: a heritable breakup.Cancer Res. 2012 Jul 1;72(13):3119-24. doi: 10.1158/0008-5472.CAN-11-3891. Epub 2012 Jun 15.
• [7] The MicroRNA-382-5p/MXD1 Axis Relates to Breast Cancer Progression and Promotes Cell Malignant Phenotypes.J Surg Res. 2020 Feb;246:442-449. doi: 10.1016/j.jss.2019.09.018. Epub 2019 Oct 18.
• [8] Effects of the MYC oncogene antagonist, MAD, on proliferation, cell cycling and the malignant phenotype of human brain tumour cells.Nat Med. 1995 Jul;1(7):638-43. doi: 10.1038/nm0795-638.
• [9] Common and specific genes and peripheral biomarkers in children and adults with attention-deficit/hyperactivity disorder.World J Biol Psychiatry. 2018 Mar;19(2):80-100. doi: 10.1080/15622975.2017.1282175. Epub 2017 Feb 24.
• [10] Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study.Lancet Oncol. 2017 Aug;18(8):1076-1088. doi: 10.1016/S1470-2045(17)30444-8. Epub 2017 Jun 28.
• [11] Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder. A study in naturalistically treated patients.Int J Neuropsychopharmacol. 2010 Nov;13(10):1369-81. doi: 10.1017/S1461145710000799. Epub 2010 Jul 15.
• [12] Mad1 suppresses bladder cancer cell proliferation by inhibiting human telomerase reverse transcriptase transcription and telomerase activity.Urology. 2006 Jun;67(6):1335-40. doi: 10.1016/j.urology.2005.12.029.
• [13] Identification of Max binding protein as a novel binding protein of Nck1 and characterization of its role in inhibiting human liver cancer SK-HEP-1 cells.Chin Med J (Engl). 2012 Sep;125(18):3336-9.
• [14] Assignment of the human MAD and MXI1 genes to chromosomes 2p12-p13 and 10q24-q25.Genomics. 1994 Sep 1;23(1):282-5. doi: 10.1006/geno.1994.1496.
• [15] Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene.Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7859-64. doi: 10.1073/pnas.1332465100. Epub 2003 Jun 16.
• [16] Unravelling the Prospective Associations Between Mixed Anxiety-Depression and Insomnia During the Course of Cognitive Behavioral Therapy.Psychosom Med. 2019 May;81(4):333-340. doi: 10.1097/PSY.0000000000000676.
• [17] APC-dependent regulation of ornithine decarboxylase in human colon tumor cells.Mol Carcinog. 2002 May;34(1):10-8. doi: 10.1002/mc.10043.
• [18] MiR-19a/b modulate the metastasis of gastric cancer cells by targeting the tumour suppressor MXD1.Cell Death Dis. 2014 Mar 27;5(3):e1144. doi: 10.1038/cddis.2014.110.
• [19] Transcriptional repression of Mad-Max complex by human umbilical cord blood stem cells downregulates extracellular signal-regulated kinase in glioblastoma.Stem Cells Dev. 2012 Jul 1;21(10):1779-93. doi: 10.1089/scd.2011.0424. Epub 2011 Nov 21.
• [20] Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C.Antimicrob Agents Chemother. 2012 Apr;56(4):1838-44. doi: 10.1128/AAC.05854-11. Epub 2012 Jan 30.
• [21] Hepatocyte transplantation improves survival in mice with liver toxicity induced by hepatic overexpression of Mad1 transcription factor.Mol Ther. 2000 Apr;1(4):358-65. doi: 10.1006/mthe.2000.0051.
• [22] Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers.Cancer Lett. 2001 Jan 26;162(2):201-5. doi: 10.1016/s0304-3835(00)00675-3.
• [23] JC virus granule cell neuronopathy is associated with VP1 C terminus mutants.J Gen Virol. 2012 Jan;93(Pt 1):175-183. doi: 10.1099/vir.0.037440-0. Epub 2011 Sep 21.
• [24] Antigen-specific IgG elicited in subjects with prostate cancer treated with flt3 ligand.J Immunother. 2005 May-Jun;28(3):268-75. doi: 10.1097/01.cji.0000158853.15664.0c.
• [25] Overexpression of the mitotic checkpoint genes BUB1 and BUBR1 is associated with genomic complexity in clear cell kidney carcinomas.Cell Oncol. 2008;30(5):389-95. doi: 10.3233/clo-2008-0439.
• [26] Oesophageal adenocarcinoma is associated with a deregulation in the MYC/MAX/MAD network.Br J Cancer. 2008 Jun 17;98(12):1985-92. doi: 10.1038/sj.bjc.6604398. Epub 2008 May 20.
• [27] Induction of chromosomal instability in colonic cells by the human polyomavirus JC virus.Cancer Res. 2003 Nov 1;63(21):7256-62.
• [28] The MAD1 1673 G ?A polymorphism alters the function of the mitotic spindle assembly checkpoint and is associated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer.Pharmacogenet Genomics. 2013 Apr;23(4):190-9. doi: 10.1097/FPC.0b013e32835ea08a.
• [29] SIRT1 regulates Mxd1 during malignant melanoma progression.Oncotarget. 2017 Oct 3;8(70):114540-114553. doi: 10.18632/oncotarget.21457. eCollection 2017 Dec 29.
• [30] Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma.Nat Genet. 2011 Jun 19;43(7):663-7. doi: 10.1038/ng.861.
• [31] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [32] 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.
• [33] Analysis of telomerase activity and RNA expression in a patient with acute promyelocytic leukemia treated with all-trans retinoic acid. Pediatr Blood Cancer. 2006 Apr;46(4):506-11. doi: 10.1002/pbc.20392.
• [34] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [35] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [36] 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.
• [37] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [38] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [39] Vitamin D receptor as a master regulator of the c-MYC/MXD1 network. Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):18827-32. doi: 10.1073/pnas.1210037109. Epub 2012 Oct 29.
• [40] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [41] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [42] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [43] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [44] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [45] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [46] Prediction of the contact sensitizing potential of chemicals using analysis of gene expression changes in human THP-1 monocytes. Toxicol Lett. 2010 Nov 10;199(1):51-9.
• [47] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [48] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [49] 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.
• [50] Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther. 2005 Feb;4(2):233-41.
• [51] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [52] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [53] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [54] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [55] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [56] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [57] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [58] 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.
• [59] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [60] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.