Details of Drug Off-Target (DOT)

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

• DOT Name: Calcineurin subunit B type 1 (PPP3R1)
• Synonyms: Protein phosphatase 2B regulatory subunit 1; Protein phosphatase 3 regulatory subunit B alpha isoform 1
• Gene Name: PPP3R1
• Related Disease:
  Alzheimer disease
  Amyloidosis
  Breast cancer
  Breast carcinoma
  Colitis
  Cornea plana
  High blood pressure
  Myocardial ischemia
  Psoriasis
  Schizophrenia
  Advanced cancer
  Coronary heart disease
  Neuroblastoma
  Paraplegia
  Parkinson disease
• UniProt ID: CANB1_HUMAN
• PDB ID: 1AUI; 1M63; 1MF8; 2P6B; 3LL8; 4F0Z; 4OR9; 4ORA; 4ORC; 5SVE; 6NUC; 6NUF; 6NUU; 7U0T
• Pfam ID: PF13499
• Sequence:
  MGNEASYPLEMCSHFDADEIKRLGKRFKKLDLDNSGSLSVEEFMSLPELQQNPLVQRVID
  IFDTDGNGEVDFKEFIEGVSQFSVKGDKEQKLRFAFRIYDMDKDGYISNGELFQVLKMMV
  GNNLKDTQLQQIVDKTIINADKDGDGRISFEEFCAVVGGLDIHKKMVVDV
• Function: Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Oocyte meiosis (hsa04114)
  Cellular senescence (hsa04218)
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
  VEGF sig.ling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  C-type lectin receptor sig.ling pathway (hsa04625)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Long-term potentiation (hsa04720)
  Glutamatergic sy.pse (hsa04724)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Renin secretion (hsa04924)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Amphetamine addiction (hsa05031)
  Tuberculosis (hsa05152)
  Human cytomegalovirus infection (hsa05163)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  DARPP-32 events (R-HSA-180024)
  Calcineurin activates NFAT (R-HSA-2025928)
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  Ca2+ pathway (R-HSA-4086398)
  CLEC7A (Dectin-1) induces NFAT activation (R-HSA-5607763)
  Activation of BAD and translocation to mitochondria (R-HSA-111447)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Amyloidosis	DISHTAI2	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Colitis	DISAF7DD	Strong	Biomarker	[4]
Cornea plana	DISE38HI	Strong	Genetic Variation	[5]
High blood pressure	DISY2OHH	Strong	Biomarker	[6]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[7]
Psoriasis	DIS59VMN	Strong	Biomarker	[8]
Schizophrenia	DISSRV2N	Strong	Biomarker	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[10]
Coronary heart disease	DIS5OIP1	Disputed	Genetic Variation	[11]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[12]
Paraplegia	DISSKWBI	Limited	Biomarker	[13]
Parkinson disease	DISQVHKL	Limited	Biomarker	[12]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Calcineurin subunit B type 1 (PPP3R1) increases the Nephropathy toxic ADR of Ciclosporin.	[24]
Tacrolimus	DMZ7XNQ	Approved	Calcineurin subunit B type 1 (PPP3R1) increases the Nephropathy toxic ADR of Tacrolimus.	[24]
Cimetidine	DMH61ZB	Approved	Calcineurin subunit B type 1 (PPP3R1) increases the Hyperparathyroidism secondary ADR of Cimetidine.	[24]
Sirolimus	DMGW1ID	Approved	Calcineurin subunit B type 1 (PPP3R1) increases the Nephropathy toxic ADR of Sirolimus.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Calcineurin subunit B type 1 (PPP3R1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcineurin subunit B type 1 (PPP3R1).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Calcineurin subunit B type 1 (PPP3R1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Calcineurin subunit B type 1 (PPP3R1).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calcineurin subunit B type 1 (PPP3R1).	[18]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Calcineurin subunit B type 1 (PPP3R1).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Calcineurin subunit B type 1 (PPP3R1).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Calcineurin subunit B type 1 (PPP3R1).	[21]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Calcineurin subunit B type 1 (PPP3R1).	[22]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Calcineurin subunit B type 1 (PPP3R1).	[23]

References

• [1] CNB-001, a synthetic pyrazole derivative of curcumin, suppresses lipopolysaccharide-induced nitric oxide production through the inhibition of NF-B and p38 MAPK pathways in microglia.Eur J Pharmacol. 2018 Jan 15;819:190-197. doi: 10.1016/j.ejphar.2017.12.008. Epub 2017 Dec 6.
• [2] Modulation of 5-lipoxygenase in proteotoxicity and Alzheimer's disease.J Neurosci. 2013 Jun 19;33(25):10512-25. doi: 10.1523/JNEUROSCI.5183-12.2013.
• [3] Meta-analysis of the diagnostic accuracy of ultrasound-guided fine-needle aspiration and core needle biopsy in diagnosing axillary lymph node metastasis.Br J Surg. 2018 Sep;105(10):1244-1253. doi: 10.1002/bjs.10920. Epub 2018 Jul 4.
• [4] Calcineurin-mediated IL-2 production by CD11c(high)MHCII(+) myeloid cells is crucial for intestinal immune homeostasis.Nat Commun. 2018 Mar 16;9(1):1102. doi: 10.1038/s41467-018-03495-3.
• [5] Dominantly and recessively inherited cornea plana congenita map to the same small region of chromosome 12.Genome Res. 1996 Apr;6(4):249-54. doi: 10.1101/gr.6.4.249.
• [6] Genome Wide Analysis Approach Suggests Chromosome 2 Locus to be Associated with Thiazide and Thiazide Like-Diuretics Blood Pressure Response.Sci Rep. 2019 Nov 21;9(1):17323. doi: 10.1038/s41598-019-53345-5.
• [7] 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.
• [8] MiR-548a-3p Promotes Keratinocyte Proliferation Targeting PPP3R1 after Being Induced by IL-22.Inflammation. 2018 Mar;41(2):496-504. doi: 10.1007/s10753-017-0705-3.
• [9] Calcineurin knockout mice show a selective loss of small spines.Neurosci Lett. 2018 Apr 3;671:99-102. doi: 10.1016/j.neulet.2018.02.006. Epub 2018 Feb 7.
• [10] Utility of core biopsy with concurrent ROSE FNA in the diagnosis of pancreatic tumor-does the biopsy add any diagnostic benefit?.Diagn Cytopathol. 2018 Feb;46(2):154-159. doi: 10.1002/dc.23870. Epub 2017 Dec 11.
• [11] Association of CnB 5I/5D promoter gene polymorphism and serum calcineurin levels in early onset of coronary artery disease of south Indian cohort.Gene. 2017 Oct 20;632:1-6. doi: 10.1016/j.gene.2017.08.002. Epub 2017 Aug 4.
• [12] Neuroprotective effect of CNB-001, a novel pyrazole derivative of curcumin on biochemical and apoptotic markers against rotenone-induced SK-N-SH cellular model of Parkinson's disease.J Mol Neurosci. 2013 Nov;51(3):863-70. doi: 10.1007/s12031-013-0075-8. Epub 2013 Jul 31.
• [13] CNB-001 reduces paraplegia in rabbits following spinal cord ischemia.Neural Regen Res. 2019 Dec;14(12):2192-2198. doi: 10.4103/1673-5374.262598.
• [14] 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.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [18] 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.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] 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.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.
• [23] 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.
• [24] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.