Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1VTUL9)

• DOT Name: Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B)
• Synonyms: SMEK homolog 2
• Gene Name: PPP4R3B
• Related Disease: Vitiligo
• UniProt ID: P4R3B_HUMAN
• Pfam ID: PF04802
• Sequence:
  MSDTRRRVKVYTLNEDRQWDDRGTGHVSSTYVEELKGMSLLVRAESDGSLLLESKINPNT
  AYQKQQDTLIVWSEAENYDLALSFQEKAGCDEIWEKICQVQGKDPSVEVTQDLIDESEEE
  RFEEMPETSHLIDLPTCELNKLEEIADLVTSVLSSPIRREKLALALENEGYIKKLLQLFQ
  ACENLENTEGLHHLYEIIRGILFLNKATLFEVMFSDECIMDVVGCLEYDPALAQPKRHRE
  FLTKTAKFKEVIPITDSELRQKIHQTYRVQYIQDIILPTPSVFEENFLSTLTSFIFFNKV
  EIVSMLQEDEKFLSEVFAQLTDEATDDDKRRELVNFFKEFCAFSQTLQPQNRDAFFKTLA
  KLGILPALEIVMGMDDLQVRSAATDIFSYLVEFSPSMVREFVMQEAQQSDDDILLINVVI
  EQMICDTDPELGGAVQLMGLLRTLIDPENMLATTNKTEKSEFLNFFYNHCMHVLTAPLLT
  NTSEDKCEKDFFLKHYRYSWSFICTPSHSHSHSTPSSSISQDNIVGSNKNNTICPDNYQT
  AQLLALILELLTFCVEHHTYHIKNYIMNKDLLRRVLVLMNSKHTFLALCALRFMRRIIGL
  KDEFYNRYITKGNLFEPVINALLDNGTRYNLLNSAVIELFEFIRVEDIKSLTAHIVENFY
  KALESIEYVQTFKGLKTKYEQEKDRQNQKLNSVPSILRSNRFRRDAKALEEDEEMWFNED
  EEEEGKAVVAPVEKPKPEDDFPDNYEKFMETKKAKESEDKENLPKRTSPGGFKFTFSHSA
  SAANGTNSKSVVAQIPPATSNGSSSKTTNLPTSVTATKGSLVGLVDYPDDEEEDEEEESS
  PRKRPRLGS
• Function: Regulatory subunit of serine/threonine-protein phosphatase 4 (PP4). May regulate the activity of PPP4C at centrosomal microtubule organizing centers.
• Tissue Specificity: Moderately expressed in tissues and specific brain regions examined.
• KEGG Pathway: Glucagon sig.ling pathway (hsa04922)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Vitiligo	DISR05SL	Strong	Genetic Variation	[1]

12 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 Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Serine/threonine-protein phosphatase 4 regulatory subunit 3B (PPP4R3B).	[12]

References

• [1] Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.Nat Genet. 2016 Nov;48(11):1418-1424. doi: 10.1038/ng.3680. Epub 2016 Oct 10.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.