Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZMH6V3)

• DOT Name: Protein phosphatase 1B (PPM1B)
• Synonyms: EC 3.1.3.16; Protein phosphatase 2C isoform beta; PP2C-beta
• Gene Name: PPM1B
• Related Disease:
  Breast cancer
  Breast carcinoma
  Bladder cancer
  Coronary atherosclerosis
  Hypotonia-cystinuria syndrome
  Myocardial ischemia
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: PPM1B_HUMAN
• PDB ID: 2P8E
• EC Number: 3.1.3.16
• Pfam ID: PF00481 ; PF07830
• Sequence:
  MGAFLDKPKTEKHNAHGAGNGLRYGLSSMQGWRVEMEDAHTAVVGIPHGLEDWSFFAVYD
  GHAGSRVANYCSTHLLEHITTNEDFRAAGKSGSALELSVENVKNGIRTGFLKIDEYMRNF
  SDLRNGMDRSGSTAVGVMISPKHIYFINCGDSRAVLYRNGQVCFSTQDHKPCNPREKERI
  QNAGGSVMIQRVNGSLAVSRALGDYDYKCVDGKGPTEQLVSPEPEVYEILRAEEDEFIIL
  ACDGIWDVMSNEELCEYVKSRLEVSDDLENVCNWVVDTCLHKGSRDNMSIVLVCFSNAPK
  VSDEAVKKDSELDKHLESRVEEIMEKSGEEGMPDLAHVMRILSAENIPNLPPGGGLAGKR
  NVIEAVYSRLNPHRESDGASDEAEESGSQGKLVEALRQMRINHRGNYRQLLEEMLTSYRL
  AKVEGEESPAEPAATATSSNSDAGNPVTMQESHTESESGLAELDSSNEDAGTKMSGEKI
• Function: Enzyme with a broad specificity. Dephosphorylates CDK2 and CDK6 in vitro. Dephosphorylates PRKAA1 and PRKAA2. Inhibits TBK1-mediated antiviral signaling by dephosphorylating it at 'Ser-172'. Plays an important role in the termination of TNF-alpha-mediated NF-kappa-B activation through dephosphorylating and inactivating IKBKB/IKKB.
• Tissue Specificity: Highly expressed in heart and skeletal muscle.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)
• Reactome Pathway:
  ALK mutants bind TKIs (R-HSA-9700645)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[3]
Hypotonia-cystinuria syndrome	DISUPMRI	Strong	Genetic Variation	[4]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[5]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein phosphatase 1B (PPM1B).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein phosphatase 1B (PPM1B).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein phosphatase 1B (PPM1B).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein phosphatase 1B (PPM1B).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein phosphatase 1B (PPM1B).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein phosphatase 1B (PPM1B).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein phosphatase 1B (PPM1B).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Protein phosphatase 1B (PPM1B).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Protein phosphatase 1B (PPM1B).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein phosphatase 1B (PPM1B).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protein phosphatase 1B (PPM1B).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein phosphatase 1B (PPM1B).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein phosphatase 1B (PPM1B).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Protein phosphatase 1B (PPM1B).	[18]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Protein phosphatase 1B (PPM1B).	[19]

References

• [1] PPM1B depletion in U2OS cells supresses cell growth through RB1-E2F1 pathway and stimulates bleomycin-induced cell death.Biochem Biophys Res Commun. 2018 Jun 2;500(2):391-397. doi: 10.1016/j.bbrc.2018.04.084. Epub 2018 Apr 19.
• [2] miR-186 downregulates protein phosphatase PPM1B in bladder cancer and mediates G1-S phase transition.Tumour Biol. 2016 Apr;37(4):4331-41. doi: 10.1007/s13277-015-4117-4. Epub 2015 Oct 23.
• [3] Potentially critical roles of TNPO1, RAP1B, ZDHHC17, and PPM1B in the progression of coronary atherosclerosis through microarray data analysis.J Cell Biochem. 2019 Mar;120(3):4301-4311. doi: 10.1002/jcb.27715. Epub 2018 Sep 30.
• [4] PREPL deficiency: delineation of the phenotype and development of a functional blood assay. Genet Med. 2018 Jan;20(1):109-118. doi: 10.1038/gim.2017.74. Epub 2017 Jul 20.
• [5] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] 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.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] 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.
• [18] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [19] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.