Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKSVU7S)

• DOT Name: Protein phosphatase 1H (PPM1H)
• Synonyms: EC 3.1.3.16
• Gene Name: PPM1H
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Neoplasm
  Pancreatic cancer
  Parkinson disease
  Adenocarcinoma
  Colon cancer
  Colon carcinoma
• UniProt ID: PPM1H_HUMAN
• PDB ID: 7KPR; 7L4I; 7L4J; 7N0Z
• EC Number: 3.1.3.16
• Pfam ID: PF00481
• Sequence:
  MLTRVKSAVANFMGGIMAGSSGSEHGGGSCGGSDLPLRFPYGRPEFLGLSQDEVECSADH
  IARPILILKETRRLPWATGYAEVINAGKSTHNEDQASCEVLTVKKKAGAVTSTPNRNSSK
  RRSSLPNGEGLQLKENSESEGVSCHYWSLFDGHAGSGAAVVASRLLQHHITEQLQDIVDI
  LKNSAVLPPTCLGEEPENTPANSRTLTRAASLRGGVGAPGSPSTPPTRFFTEKKIPHECL
  VIGALESAFKEMDLQIERERSSYNISGGCTALIVICLLGKLYVANAGDSRAIIIRNGEII
  PMSSEFTPETERQRLQYLAFMQPHLLGNEFTHLEFPRRVQRKELGKKMLYRDFNMTGWAY
  KTIEDEDLKFPLIYGEGKKARVMATIGVTRGLGDHDLKVHDSNIYIKPFLSSAPEVRIYD
  LSKYDHGSDDVLILATDGLWDVLSNEEVAEAITQFLPNCDPDDPHRYTLAAQDLVMRARG
  VLKDRGWRISNDRLGSGDDISVYVIPLIHGNKLS
• Function: Dephosphorylates CDKN1B at 'Thr-187', thus removing a signal for proteasomal degradation.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Pancreatic cancer	DISJC981	Strong	Biomarker	[3]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[4]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[5]
Colon cancer	DISVC52G	Limited	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Limited	Altered Expression	[5]

15 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 phosphatase 1H (PPM1H).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein phosphatase 1H (PPM1H).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein phosphatase 1H (PPM1H).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein phosphatase 1H (PPM1H).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein phosphatase 1H (PPM1H).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein phosphatase 1H (PPM1H).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein phosphatase 1H (PPM1H).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Protein phosphatase 1H (PPM1H).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein phosphatase 1H (PPM1H).	[14]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Protein phosphatase 1H (PPM1H).	[15]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Protein phosphatase 1H (PPM1H).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein phosphatase 1H (PPM1H).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein phosphatase 1H (PPM1H).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein phosphatase 1H (PPM1H).	[22]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Protein phosphatase 1H (PPM1H).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein phosphatase 1H (PPM1H).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Protein phosphatase 1H (PPM1H).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein phosphatase 1H (PPM1H).	[21]

References

• [1] PPM1H is a p27 phosphatase implicated in trastuzumab resistance.Cancer Discov. 2011 Sep;1(4):326-37. doi: 10.1158/2159-8290.CD-11-0062. Epub 2011 Jul 20.
• [2] Low tumour PPM1H indicates poor prognosis in colorectal cancer via activation of cancer-associated fibroblasts.Br J Cancer. 2019 May;120(10):987-995. doi: 10.1038/s41416-019-0450-5. Epub 2019 Apr 16.
• [3] Effect of PPM1H on malignant phenotype of human pancreatic cancer cells.Oncol Rep. 2016 Nov;36(5):2926-2934. doi: 10.3892/or.2016.5065. Epub 2016 Sep 5.
• [4] PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins.Elife. 2019 Oct 30;8:e50416. doi: 10.7554/eLife.50416.
• [5] Protein phosphatase 1H, overexpressed in colon adenocarcinoma, is associated with CSE1L.Cancer Biol Ther. 2008 Feb;7(2):285-92. doi: 10.4161/cbt.7.2.5302. Epub 2007 Nov 14.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [13] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [14] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [15] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [16] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [17] 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.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.