Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKZ0YKM)

• DOT Name: Protein max (MAX)
• Synonyms: Class D basic helix-loop-helix protein 4; bHLHd4; Myc-associated factor X
• Gene Name: MAX
• Related Disease:
  Hereditary pheochromocytoma-paraganglioma
  Pheochromocytoma
  Bacterial vaginosis
  Breast cancer
  Breast carcinoma
  Burkitt lymphoma
  Carcinoma
  Central diabetes insipidus
  Cholestasis
  Clear cell renal carcinoma
  Colon cancer
  Colorectal carcinoma
  Depression
  Endometrial cancer
  Endometrial carcinoma
  Gastrointestinal stromal tumour
  Glioblastoma multiforme
  Gonorrhea
  Hereditary nonpolyposis colon cancer
  Kidney neoplasm
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Lynch syndrome
  Multiple endocrine neoplasia type 2
  Neuroblastoma
  Paraganglioma
  Pleural tuberculosis
  Pneumocystis pneumonia
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Von hippel-lindau disease
  Wilms tumor
  Advanced cancer
  Influenza
  Plasma cell myeloma
  Hereditary neoplastic syndrome
  Adenocarcinoma
  Barrett esophagus
  Colon carcinoma
  Coronary heart disease
  Esophageal adenocarcinoma
  Esophageal cancer
  Neuroblastic tumor
  Non-insulin dependent diabetes
  Small-cell lung cancer
• UniProt ID: MAX_HUMAN
• PDB ID: 1AN2; 1HLO; 1NKP; 1NLW; 1R05; 5EYO; 6G6J; 6G6K; 6G6L; 8OTS; 8OTT
• Pfam ID: PF00010
• Sequence:
  MSDNDDIEVESDEEQPRFQSAADKRAHHNALERKRRDHIKDSFHSLRDSVPSLQGEKASR
  AQILDKATEYIQYMRRKNHTHQQDIDDLKRQNALLEQQVRALEKARSSAQLQTNYPSSDN
  SLYTNAKGSTISAFDGGSDSSSESEPEEPQSRKKLRMEAS
• Function: Transcription regulator. Forms a sequence-specific DNA-binding protein complex with MYC or MAD which recognizes the core sequence 5'-CAC[GA]TG-3'. The MYC:MAX complex is a transcriptional activator, whereas the MAD:MAX complex is a repressor. May repress transcription via the recruitment of a chromatin remodeling complex containing H3 'Lys-9' histone methyltransferase activity. Represses MYC transcriptional activity from E-box elements.
• Tissue Specificity: High levels found in the brain, heart and lung while lower levels are seen in the liver, kidney and skeletal muscle.
• KEGG Pathway:
  Polycomb repressive complex (hsa03083)
  MAPK sig.ling pathway (hsa04010)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  Cyclin E associated events during G1/S transition (R-HSA-69202)
  Cyclin A (R-HSA-69656)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  Transcription of E2F targets under negative control by DREAM complex (R-HSA-1362277)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary pheochromocytoma-paraganglioma	DISP9K7L	Definitive	Autosomal dominant	[1]
Pheochromocytoma	DIS56IFV	Definitive	Autosomal dominant	[2]
Bacterial vaginosis	DISK2MZ2	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[6]
Central diabetes insipidus	DISJ4P9O	Strong	Biomarker	[7]
Cholestasis	DISDJJWE	Strong	Altered Expression	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[9]
Colon cancer	DISVC52G	Strong	Genetic Variation	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Depression	DIS3XJ69	Strong	Biomarker	[12]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[13]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[13]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Genetic Variation	[14]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[15]
Gonorrhea	DISQ5AO6	Strong	Biomarker	[16]
Hereditary nonpolyposis colon cancer	DISPA49R	Strong	Biomarker	[17]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[18]
Lung carcinoma	DISTR26C	Strong	Biomarker	[18]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[19]
Lynch syndrome	DIS3IW5F	Strong	Biomarker	[17]
Multiple endocrine neoplasia type 2	DISPQ4Y5	Strong	Genetic Variation	[20]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[21]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[22]
Pleural tuberculosis	DISD09EG	Strong	Biomarker	[23]
Pneumocystis pneumonia	DISFSOM3	Strong	Biomarker	[24]
Prostate cancer	DISF190Y	Strong	Biomarker	[25]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[25]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[9]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Genetic Variation	[20]
Wilms tumor	DISB6T16	Strong	Biomarker	[26]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[25]
Influenza	DIS3PNU3	moderate	Biomarker	[27]
Plasma cell myeloma	DIS0DFZ0	moderate	Genetic Variation	[28]
Hereditary neoplastic syndrome	DISGXLG5	Disputed	CausalMutation	[29]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[30]
Barrett esophagus	DIS416Y7	Limited	Altered Expression	[30]
Colon carcinoma	DISJYKUO	Limited	Genetic Variation	[10]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[31]
Esophageal adenocarcinoma	DISODWFP	Limited	Altered Expression	[30]
Esophageal cancer	DISGB2VN	Limited	Altered Expression	[30]
Neuroblastic tumor	DISKWPS1	Limited	Biomarker	[32]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[33]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[34]

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 Protein max (MAX).	[35]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein max (MAX).	[36]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein max (MAX).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein max (MAX).	[38]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein max (MAX).	[39]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein max (MAX).	[40]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein max (MAX).	[41]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein max (MAX).	[42]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Protein max (MAX).	[44]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein max (MAX).	[45]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Protein max (MAX).	[46]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Protein max (MAX).	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein max (MAX).	[43]

References

• [1] 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.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Diagnostic performance of two molecular assays for the detection of vaginitis in symptomatic women.Eur J Clin Microbiol Infect Dis. 2020 Jan;39(1):39-44. doi: 10.1007/s10096-019-03694-w. Epub 2019 Sep 9.
• [4] Plasma Metabolomic Signatures Associated with Long-term Breast Cancer Risk in the SU.VI.MAX Prospective Cohort.Cancer Epidemiol Biomarkers Prev. 2019 Aug;28(8):1300-1307. doi: 10.1158/1055-9965.EPI-19-0154. Epub 2019 Jun 4.
• [5] MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells.Cancer Res. 2007 Oct 15;67(20):9762-70. doi: 10.1158/0008-5472.CAN-07-2462.
• [6] Profiling of Discrete Gynecological Cancers Reveals Novel Transcriptional Modules and Common Features Shared by Other Cancer Types and Embryonic Stem Cells.PLoS One. 2015 Nov 11;10(11):e0142229. doi: 10.1371/journal.pone.0142229. eCollection 2015.
• [7] Evaluation of a nucleic acid amplification assay for the diagnosis of Clostridioides difficile infection.Anaerobe. 2019 Oct;59:201-204. doi: 10.1016/j.anaerobe.2019.06.015. Epub 2019 Jun 27.
• [8] Prohibitin 1 suppresses liver cancer tumorigenesis in mice and human hepatocellular and cholangiocarcinoma cells.Hepatology. 2017 Apr;65(4):1249-1266. doi: 10.1002/hep.28964. Epub 2017 Jan 31.
• [9] Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review.J Clin Endocrinol Metab. 2017 Nov 1;102(11):4013-4022. doi: 10.1210/jc.2017-00562.
• [10] c-Myc inactivation by mutant Max alters growth and morphology of NCI-H-630 colon cancer cells.J Cell Physiol. 1996 Oct;169(1):200-8. doi: 10.1002/(SICI)1097-4652(199610)169:1<200::AID-JCP20>3.0.CO;2-F.
• [11] Right or Left Primary Site of Colorectal Cancer: Outcomes From the Molecular Analysis of the AGITG MAX Trial.Clin Colorectal Cancer. 2019 Jun;18(2):141-148. doi: 10.1016/j.clcc.2018.12.002. Epub 2019 Jan 3.
• [12] Assessing cancer-specific anxiety in Chinese men with prostate cancer: psychometric evaluation of the Chinese version of the Memorial Anxiety Scale for Prostate Cancer (MAX-PC).Support Care Cancer. 2017 Dec;25(12):3683-3690. doi: 10.1007/s00520-017-3794-5. Epub 2017 Jun 22.
• [13] MAX Mutations in Endometrial Cancer: Clinicopathologic Associations and Recurrent MAX p.His28Arg Functional Characterization.J Natl Cancer Inst. 2018 May 1;110(5):517-526. doi: 10.1093/jnci/djx238.
• [14] Identifying Secondary Mutations in Chinese Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs) by Next Generation Sequencing (NGS).Pathol Oncol Res. 2020 Jan;26(1):91-100. doi: 10.1007/s12253-019-00770-6. Epub 2019 Nov 22.
• [15] c-myc oncogene family expression in glioblastoma and survival.Surg Neurol. 1999 May;51(5):536-42. doi: 10.1016/s0090-3019(98)00028-7.
• [16] Evaluation of the BD MAX?Vaginal Panel for the detection of vaginal infections in a sexual health service in the UK.Int J STD AIDS. 2019 Mar;30(4):411-414. doi: 10.1177/0956462418815284. Epub 2019 Jan 8.
• [17] Mutation and association analyses of the candidate genes ESR1, ESR2, MAX, PCNA, and KAT2A in patients with unexplained MSH2-deficient tumors.Fam Cancer. 2012 Mar;11(1):19-26. doi: 10.1007/s10689-011-9489-z.
• [18] A three-platelet mRNA set: MAX, MTURN and HLA-B as biomarker for lung cancer.J Cancer Res Clin Oncol. 2019 Nov;145(11):2713-2723. doi: 10.1007/s00432-019-03032-9. Epub 2019 Sep 24.
• [19] Synergistic induction of the Fas (CD95) ligand promoter by Max and NFkappaB in human non-small lung cancer cells.Exp Cell Res. 2004 Sep 10;299(1):227-35. doi: 10.1016/j.yexcr.2004.05.031.
• [20] Extent of surgery for phaeochromocytomas in the genomic era.Br J Surg. 2018 Jan;105(2):e84-e98. doi: 10.1002/bjs.10744.
• [21] MAX to MYCN intracellular ratio drives the aggressive phenotype and clinical outcome of high risk neuroblastoma.Biochim Biophys Acta Gene Regul Mech. 2018 Mar;1861(3):235-245. doi: 10.1016/j.bbagrm.2018.01.007. Epub 2018 Feb 3.
• [22] Malignant Intrarenal/Renal Pelvis Paraganglioma with Co-Occurring SDHB and ATRX Mutations.Endocr Pathol. 2019 Dec;30(4):270-275. doi: 10.1007/s12022-019-09594-1.
• [23] The Performance of Pleural Fluid T-SPOT.TB Assay for Diagnosing Tuberculous Pleurisy in China: A Two-Center Prospective Cohort Study.Front Cell Infect Microbiol. 2019 Jan 30;9:10. doi: 10.3389/fcimb.2019.00010. eCollection 2019.
• [24] Evaluation of the automated Becton Dickinson MAX real-time PCR platform for detection of Pneumocystis jirovecii.Future Microbiol. 2017 Jan;12:29-37. doi: 10.2217/fmb-2016-0115. Epub 2016 Dec 12.
• [25] Italian cultural adaptation of the Memorial Anxiety for Prostate Cancer scale for the population of men on active surveillance.Tumori. 2018 Jun;104(3):172-178. doi: 10.5301/tj.5000646. Epub 2018 May 9.
• [26] A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.Nat Genet. 2017 Oct;49(10):1487-1494. doi: 10.1038/ng.3940. Epub 2017 Aug 21.
• [27] Comparative evaluation of the CerTest VIASURE flu A, B & RSV real time RT-PCR detection kit on the BD MAX system versus a routine in-house assay for detection of influenza A and B virus during the 2016/17 influenza season.J Clin Virol. 2018 Feb-Mar;99-100:35-37. doi: 10.1016/j.jcv.2017.12.010. Epub 2017 Dec 21.
• [28] MAX is an epigenetic sensor of 5-carboxylcytosine and is altered in multiple myeloma.Nucleic Acids Res. 2017 Mar 17;45(5):2396-2407. doi: 10.1093/nar/gkw1184.
• [29] Pathological and Genetic Characterization of Bilateral Adrenomedullary Hyperplasia in a Patient with Germline MAX Mutation.Endocr Pathol. 2017 Dec;28(4):302-307. doi: 10.1007/s12022-016-9460-5.
• [30] 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.
• [31] Integrated microRNAgene analysis of coronary artery disease based on miRNA and gene expression profiles.Mol Med Rep. 2016 Apr;13(4):3063-73. doi: 10.3892/mmr.2016.4936. Epub 2016 Feb 23.
• [32] Exome sequencing identifies predisposing and fusion gene in ganglioneuroma, ganglioneuroblastoma and neuroblastoma.Math Biosci Eng. 2019 Aug 8;16(6):7217-7229. doi: 10.3934/mbe.2019362.
• [33] Landscape of the relationship between type 2 diabetes and coronary heart disease through an integrated gene network analysis.Gene. 2014 Apr 10;539(1):30-6. doi: 10.1016/j.gene.2014.02.001. Epub 2014 Feb 5.
• [34] MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1.Cancer Discov. 2014 Mar;4(3):292-303. doi: 10.1158/2159-8290.CD-13-0799. Epub 2013 Dec 20.
• [35] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [36] 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.
• [37] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [38] 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.
• [39] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [40] Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. Oncotarget. 2015 Aug 28;6(25):21493-506. doi: 10.18632/oncotarget.4085.
• [41] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [42] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [43] 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.
• [44] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [45] 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.
• [46] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [47] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.