Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQA4DDN)

• DOT Name: Mastermind-like protein 1 (MAML1)
• Synonyms: Mam-1
• Gene Name: MAML1
• Related Disease:
  Advanced cancer
  Angiosarcoma
  Arteriosclerosis
  Atherosclerosis
  Carcinoma of esophagus
  Clear cell renal carcinoma
  Esophageal cancer
  Kidney cancer
  Neoplasm
  Neoplasm of esophagus
  Renal carcinoma
  Renal cell carcinoma
  T-cell acute lymphoblastic leukaemia
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Head-neck squamous cell carcinoma
  Liver cancer
  Melanoma
  Rhabdomyosarcoma
  Esophageal squamous cell carcinoma
  Congenital contractural arachnodactyly
• UniProt ID: MAML1_HUMAN
• PDB ID: 2F8X; 3NBN; 3V79; 6SMV
• Pfam ID: PF09596 ; PF20802 ; PF20801
• Sequence:
  MVLPTCPMAEFALPRHSAVMERLRRRIELCRRHHSTCEARYEAVSPERLELERQHTFALH
  QRCIQAKAKRAGKHRQPPAATAPAPAAPAPRLDAADGPEHGRPATHLHDTVKRNLDSATS
  PQNGDQQNGYGDLFPGHKKTRREAPLGVAISSNGLPPASPLGQSDKPSGADALQSSGKHS
  LGLDSLNKKRLADSSLHLNGGSNPSESFPLSLNKELKQEPVEDLPCMITGTVGSISQSNL
  MPDLNLNEQEWKELIEELNRSVPDEDMKDLFNEDFEEKKDPESSGSATQTPLAQDINIKT
  EFSPAAFEQEQLGSPQVRAGSAGQTFLGPSSAPVSTDSPSLGGSQTLFHTSGQPRADNPS
  PNLMPASAQAQNAQRALAGVVLPSQGPGGASELSSAHQLQQIAAKQKREQMLQNPQQATP
  APAPGQMSTWQQTGPSHSSLDVPYPMEKPASPSSYKQDFTNSKLLMMPSVNKSSPRPGGP
  YLQPSHVNLLSHQPPSNLNQNSANNQGSVLDYGNTKPLSHYKADCGQGSPGSGQSKPALM
  AYLPQQLSHISHEQNSLFLMKPKPGNMPFRSLVPPGQEQNPSSVPVQAQATSVGTQPPAV
  SVASSHNSSPYLSSQQQAAVMKQHQLLLDQQKQREQQQKHLQQQQFLQRQQHLLAEQEKQ
  QFQRHLTRPPPQYQDPTQGSFPQQVGQFTGSSAAVPGMNTLGPSNSSCPRVFPQAGNLMP
  MGPGHASVSSLPTNSGQQDRGVAQFPGSQNMPQSSLYGMASGITQIVAQPPPQATNGHAH
  IPRQTNVGQNTSVSAAYGQNSLGSSGLSQQHNKGTLNPGLTKPPVPRVSPAMGGQNSSWQ
  HQGMPNLSGQTPGNSNVSPFTAASSFHMQQQAHLKMSSPQFSQAVPNRPMAPMSSAAAVG
  SLLPPVSAQQRTSAPAPAPPPTAPQQGLPGLSPAGPELGAFSQSPASQMGGRAGLHCTQA
  YPVRTAGQELPFAYSGQPGGSGLSSVAGHTDLIDSLLKNRTSEEWMSDLDDLLGSQ
• Function: Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Enhances phosphorylation and proteolytic turnover of the NOTCH intracellular domain in the nucleus through interaction with CDK8. Binds to CREBBP/CBP which promotes nucleosome acetylation at NOTCH enhancers and activates transcription. Induces phosphorylation and localization of CREBBP to nuclear foci. Plays a role in hematopoietic development by regulating NOTCH-mediated lymphoid cell fate decisions.
• Tissue Specificity: Widely expressed with highest levels in heart, pancreas, peripheral blood leukocytes and spleen.
• KEGG Pathway:
  Notch sig.ling pathway (hsa04330)
  Th1 and Th2 cell differentiation (hsa04658)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells (R-HSA-210744)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  NOTCH2 intracellular domain regulates transcription (R-HSA-2197563)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Notch-HLH transcription pathway (R-HSA-350054)
  RUNX3 regulates NOTCH signaling (R-HSA-8941856)
  NOTCH3 Intracellular Domain Regulates Transcription (R-HSA-9013508)
  NOTCH4 Intracellular Domain Regulates Transcription (R-HSA-9013695)
  Formation of paraxial mesoderm (R-HSA-9793380)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Angiosarcoma	DISIYS9W	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[4]
Kidney cancer	DISBIPKM	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[4]
Renal carcinoma	DISER9XT	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[6]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[8]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[8]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Altered Expression	[9]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[10]
Liver cancer	DISDE4BI	moderate	Altered Expression	[9]
Melanoma	DIS1RRCY	moderate	Altered Expression	[11]
Rhabdomyosarcoma	DISNR7MS	moderate	Altered Expression	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Disputed	Biomarker	[4]
Congenital contractural arachnodactyly	DISOM1K7	Limited	Biomarker	[13]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Mastermind-like protein 1 (MAML1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mastermind-like protein 1 (MAML1).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Mastermind-like protein 1 (MAML1).	[16]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Mastermind-like protein 1 (MAML1).	[17]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Mastermind-like protein 1 (MAML1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mastermind-like protein 1 (MAML1).	[20]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Mastermind-like protein 1 (MAML1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Mastermind-like protein 1 (MAML1).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Mastermind-like protein 1 (MAML1).	[21]

References

• [1] Contribution of MAML1 in esophageal squamous cell carcinoma tumorigenesis.Ann Diagn Pathol. 2017 Apr;27:79-82. doi: 10.1016/j.anndiagpath.2017.01.010. Epub 2017 Feb 1.
• [2] The miR-17-92 cluster and its target THBS1 are differentially expressed in angiosarcomas dependent on MYC amplification.Genes Chromosomes Cancer. 2012 Jun;51(6):569-78. doi: 10.1002/gcc.21943. Epub 2012 Mar 2.
• [3] miR-133b Downregulation Reduces Vulnerable Plaque Formation in Mice with AS through Inhibiting Macrophage Immune Responses.Mol Ther Nucleic Acids. 2019 Jun 7;16:745-757. doi: 10.1016/j.omtn.2019.04.024. Epub 2019 May 2.
• [4] Role of MAML1 in targeted therapy against the esophageal cancer stem cells.J Transl Med. 2019 Apr 16;17(1):126. doi: 10.1186/s12967-019-1876-5.
• [5] Genetic alteration in notch pathway is associated with better prognosis in renal cell carcinoma.Biofactors. 2016 Jan-Feb;42(1):41-8. doi: 10.1002/biof.1250. Epub 2015 Dec 10.
• [6] MAML1 acts cooperatively with EGR1 to activate EGR1-regulated promoters: implications for nephrogenesis and the development of renal cancer.PLoS One. 2012;7(9):e46001. doi: 10.1371/journal.pone.0046001. Epub 2012 Sep 27.
• [7] Knockdown of MAML1 inhibits proliferation and induces apoptosis of T-cell acute lymphoblastic leukemia cells through SP1-dependent inactivation of TRIM59.J Cell Physiol. 2019 Apr;234(4):5186-5195. doi: 10.1002/jcp.27323. Epub 2018 Oct 28.
• [8] MAML1 regulates EMT markers expression through NOTCH-independent pathway in breast cancer cell line MCF7.Biochem Biophys Res Commun. 2019 Mar 12;510(3):376-382. doi: 10.1016/j.bbrc.2019.01.101. Epub 2019 Feb 4.
• [9] Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice.Gastroenterology. 2012 Dec;143(6):1660-1669.e7. doi: 10.1053/j.gastro.2012.09.002. Epub 2012 Sep 11.
• [10] MAML1 and TWIST1 co-overexpression promote invasion of head and neck squamous cell carcinoma.Asia Pac J Clin Oncol. 2018 Oct;14(5):e434-e441. doi: 10.1111/ajco.12843. Epub 2018 Jan 15.
• [11] A knockdown of Maml1 that results in melanoma cell senescence promotes an innate and adaptive immune response.Cancer Immunol Immunother. 2013 Jan;62(1):183-90. doi: 10.1007/s00262-012-1318-1. Epub 2012 Aug 5.
• [12] Notch pathway inhibition significantly reduces rhabdomyosarcoma invasiveness and mobility in vitro.Clin Cancer Res. 2011 Feb 1;17(3):505-13. doi: 10.1158/1078-0432.CCR-10-0166. Epub 2010 Dec 21.
• [13] Corilagin suppresses cholangiocarcinoma progression through Notch signaling pathway in vitro and in vivo.Int J Oncol. 2016 May;48(5):1868-76. doi: 10.3892/ijo.2016.3413. Epub 2016 Mar 2.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [18] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.