Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ7P17Z)

• DOT Name: cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A)
• Gene Name: PRKAR2A
• Related Disease:
  Cardiovascular disease
  Parkinson disease
  Adrenocortical insufficiency
  Kallmann syndrome
  Neoplasm
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
• UniProt ID: KAP2_HUMAN
• PDB ID: 2IZX; 2KYG; 4ZP3; 5H78; 5XBY
• Pfam ID: PF00027 ; PF02197
• Sequence:
  MSHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARAPASVLPAATPRQSLG
  HPPPEPGPDRVADAKGDSESEEDEDLEVPVPSRFNRRVSVCAETYNPDEEEEDTDPRVIH
  PKTDEQRCRLQEACKDILLFKNLDQEQLSQVLDAMFERIVKADEHVIDQGDDGDNFYVIE
  RGTYDILVTKDNQTRSVGQYDNRGSFGELALMYNTPRAATIVATSEGSLWGLDRVTFRRI
  IVKNNAKKRKMFESFIESVPLLKSLEVSERMKIVDVIGEKIYKDGERIITQGEKADSFYI
  IESGEVSILIRSRTKSNKDGGNQEVEIARCHKGQYFGELALVTNKPRAASAYAVGDVKCL
  VMDVQAFERLLGPCMDIMKRNISHYEEQLVKMFGSSVDLGNLGQ
• Function: Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase.
• Tissue Specificity: Four types of regulatory chains are found: I-alpha, I-beta, II-alpha, and II-beta. Their expression varies among tissues and is in some cases constitutive and in others inducible.
• KEGG Pathway: Insulin sig.ling pathway (hsa04910)
• Reactome Pathway:
  PKA activation in glucagon signalling (R-HSA-164378)
  DARPP-32 events (R-HSA-180024)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  CREB1 phosphorylation through the activation of Adenylate Cyclase (R-HSA-442720)
  Hedgehog 'off' state (R-HSA-5610787)
  ROBO receptors bind AKAP5 (R-HSA-9010642)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  PKA activation (R-HSA-163615)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[1]
Parkinson disease	DISQVHKL	Strong	Biomarker	[2]
Adrenocortical insufficiency	DISZ0CPT	moderate	Altered Expression	[3]
Kallmann syndrome	DISO3HDG	moderate	Genetic Variation	[4]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[5]
Prostate cancer	DISF190Y	Limited	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[6]

12 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 cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[14]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[16]

5 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 increases the methylation of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[18]
Forskolin	DM6ITNG	Investigative	Forskolin increases the phosphorylation of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[19]
H-89	DM4RVGO	Investigative	H-89 decreases the phosphorylation of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[19]
8-cyclopentyltheophylline	DMMITAJ	Investigative	8-cyclopentyltheophylline increases the phosphorylation of cAMP-dependent protein kinase type II-alpha regulatory subunit (PRKAR2A).	[19]

References

• [1] Prokineticin receptors in cardiovascular function: foe or friend?.Trends Cardiovasc Med. 2009 Feb;19(2):55-60. doi: 10.1016/j.tcm.2009.04.007.
• [2] Effects of Silibinin Against Prothrombin Kringle-2-Induced Neurotoxicity in the Nigrostriatal Dopaminergic System In Vivo.J Med Food. 2019 Mar;22(3):277-285. doi: 10.1089/jmf.2018.4266. Epub 2019 Jan 11.
• [3] Circadian Rhythm of Glucocorticoid Administration Entrains Clock Genes in Immune Cells: A DREAM Trial Ancillary Study.J Clin Endocrinol Metab. 2018 Aug 1;103(8):2998-3009. doi: 10.1210/jc.2018-00346.
• [4] The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis.Physiol Rev. 2018 Apr 1;98(2):1055-1082. doi: 10.1152/physrev.00012.2017.
• [5] PKR2 and -catenin genes regulates pancreatic cancer chemosensitivity.Eur Rev Med Pharmacol Sci. 2017 Jan;21(1):48-54.
• [6] Protein kinase A type II- regulatory subunit regulates the response of prostate cancer cells to taxane treatment.Cell Cycle. 2014;13(20):3292-301. doi: 10.4161/15384101.2014.949501.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] 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.
• [10] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] 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.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [16] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [17] 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.
• [18] 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.
• [19] Resveratrol improves hepatic steatosis by inducing autophagy through the cAMP signaling pathway. Mol Nutr Food Res. 2015 Aug;59(8):1443-57. doi: 10.1002/mnfr.201500016. Epub 2015 May 28.