Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWLCW9C)

• DOT Name: Mdm2-binding protein (MTBP)
• Synonyms: hMTBP
• Gene Name: MTBP
• Related Disease:
  B-cell neoplasm
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Non-small-cell lung cancer
  Ovarian cancer
  Advanced cancer
  Gastric cancer
  Stomach cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Neoplasm
  Osteosarcoma
  Triple negative breast cancer
• UniProt ID: MTBP_HUMAN
• Pfam ID: PF14920 ; PF14919 ; PF14918
• Sequence:
  MDRYLLLVIWGEGKFPSAASREAEHGPEVSSGEGTENQPDFTAANVYHLLKRSISASINP
  EDSTFPACSVGGIPGSKKWFFAVQAIYGFYQFCSSDWQEIHFDTEKDKIEDVLQTNIEEC
  LGAVECFEEEDSNSRESLSLADLYEEAAENLHQLSDKLPAPGRAMVDIILLLSDKDPPKL
  KDYLPTVGALKHLREWYSAKITIAGNHCEINCQKIAEYLSANVVSLEDLRNVIDSKELWR
  GKIQIWERKFGFEISFPEFCLKGVTLKNFSTSNLNTDFLAKKIIPSKDKNILPKVFHYYG
  PALEFVQMIKLSDLPSCYMSDIEFELGLTNSTKQNSVLLLEQISSLCSKVGALFVLPCTI
  SNILIPPPNQLSSRKWKEYIAKKPKTISVPDVEVKGECSSYYLLLQGNGNRRCKATLIHS
  ANQINGSFALNLIHGKMKTKTEEAKLSFPFDLLSLPHFSGEQIVQREKQLANVQVLALEE
  CLKRRKLAKQPETVSVAELKSLLVLTRKHFLDYFDAVIPKMILRKMDKIKTFNILNDFSP
  VEPNSSSLMETNPLEWPERHVLQNLETFEKTKQKMRTGSLPHSSEQLLGHKEGPRDSITL
  LDAKELLKYFTSDGLPIGDLQPLPIQKGEKTFVLTPELSPGKLQVLPFEKASVCHYHGIE
  YCLDDRKALERDGGFSELQSRLIRYETQTTCTRESFPVPTVLSPLPSPVVSSDPGSVPDG
  EVLQNELRTEVSRLKRRSKDLNCLYPRKRLVKSESSESLLSQTTGNSNHYHHHVTSRKPQ
  TERSLPVTCPLVPIPSCETPKLATKTSSGQKSMHESKTSRQIKESRSQKHTRILKEVVTE
  TLKKHSITETHECFTACSQRLFEISKFYLKDLKTSRGLFEEMKKTANNNAVQVIDWVLEK
  TSKK
• Function: Inhibits cell migration in vitro and suppresses the invasive behavior of tumor cells. May play a role in MDM2-dependent p53/TP53 homeostasis in unstressed cells. Inhibits autoubiquitination of MDM2, thereby enhancing MDM2 stability. This promotes MDM2-mediated ubiquitination of p53/TP53 and its subsequent degradation.
• KEGG Pathway: Cell cycle (hsa04110)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[4]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[6]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[6]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[7]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[8]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[7]
Triple negative breast cancer	DISAMG6N	Limited	Altered Expression	[8]

12 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 Mdm2-binding protein (MTBP).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mdm2-binding protein (MTBP).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mdm2-binding protein (MTBP).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mdm2-binding protein (MTBP).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Mdm2-binding protein (MTBP).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Mdm2-binding protein (MTBP).	[13]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Mdm2-binding protein (MTBP).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mdm2-binding protein (MTBP).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mdm2-binding protein (MTBP).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Mdm2-binding protein (MTBP).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mdm2-binding protein (MTBP).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mdm2-binding protein (MTBP).	[22]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Mdm2-binding protein (MTBP).	[15]

3 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 Mdm2-binding protein (MTBP).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Mdm2-binding protein (MTBP).	[21]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Mdm2-binding protein (MTBP).	[23]

References

• [1] A deficiency in Mdm2 binding protein inhibits Myc-induced B-cell proliferation and lymphomagenesis.Oncogene. 2010 Jun 3;29(22):3287-96. doi: 10.1038/onc.2010.82. Epub 2010 Mar 22.
• [2] MTBP inhibits the Erk1/2-Elk-1 signaling in hepatocellular carcinoma.Oncotarget. 2018 Apr 20;9(30):21429-21443. doi: 10.18632/oncotarget.25117. eCollection 2018 Apr 20.
• [3] MTBP promotes migration and invasion by regulation of ZEB2-mediated epithelial-mesenchymal transition in lung cancer cells.Onco Targets Ther. 2018 Oct 10;11:6741-6756. doi: 10.2147/OTT.S167963. eCollection 2018.
• [4] A low cost PS based microfluidic platform to investigate cell cycle towards developing a therapeutic strategy for cancer.Biomed Microdevices. 2018 Jul 5;20(3):57. doi: 10.1007/s10544-018-0302-8.
• [5] MTBP inhibits migration and metastasis of hepatocellular carcinoma.Clin Exp Metastasis. 2015 Apr;32(4):301-11. doi: 10.1007/s10585-015-9706-5. Epub 2015 Mar 11.
• [6] MDM2 binding protein as a predictor of metastasis and a novel prognostic biomarker in patients with gastric cancer.Oncol Lett. 2017 Dec;14(6):6409-6416. doi: 10.3892/ol.2017.7031. Epub 2017 Sep 22.
• [7] MTBP suppresses cell migration and filopodia formation by inhibiting ACTN4.Oncogene. 2013 Jan 24;32(4):462-70. doi: 10.1038/onc.2012.69. Epub 2012 Feb 27.
• [8] MTBP is overexpressed in triple-negative breast cancer and contributes to its growth and survival.Mol Cancer Res. 2014 Sep;12(9):1216-24. doi: 10.1158/1541-7786.MCR-14-0069. Epub 2014 May 27.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [15] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [16] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] 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.
• [23] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.