Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT589JA2)

• DOT Name: cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A)
• Synonyms: Tissue-specific extinguisher 1; TSE1
• Gene Name: PRKAR1A
• Related Disease:
  Acrodysostosis 1 with or without hormone resistance
  Carney complex, type 1
  Obsolete acrodysostosis with multiple hormone resistance
  Pigmented nodular adrenocortical disease, primary, 1
  Acrodysostosis
  Carney complex
  Familial atrial myxoma
  Primary pigmented nodular adrenocortical disease
• UniProt ID: KAP0_HUMAN
• PDB ID: 5KJX; 5KJY; 5KJZ
• Pfam ID: PF00027 ; PF02197
• Sequence:
  MESGSTAASEEARSLRECELYVQKHNIQALLKDSIVQLCTARPERPMAFLREYFERLEKE
  EAKQIQNLQKAGTRTDSREDEISPPPPNPVVKGRRRRGAISAEVYTEEDAASYVRKVIPK
  DYKTMAALAKAIEKNVLFSHLDDNERSDIFDAMFSVSFIAGETVIQQGDEGDNFYVIDQG
  ETDVYVNNEWATSVGEGGSFGELALIYGTPRAATVKAKTNVKLWGIDRDSYRRILMGSTL
  RKRKMYEEFLSKVSILESLDKWERLTVADALEPVQFEDGQKIVVQGEPGDEFFIILEGSA
  AVLQRRSENEEFVEVGRLGPSDYFGEIALLMNRPRAATVVARGPLKCVKLDRPRFERVLG
  PCSDILKRNIQQYNSFVSLSV
• Function: Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.
• 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)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  ALK mutants bind TKIs (R-HSA-9700645)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  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
Acrodysostosis 1 with or without hormone resistance	DISMLLJ7	Definitive	Autosomal dominant	[1]
Carney complex, type 1	DISS5310	Definitive	Autosomal dominant	[2]
Obsolete acrodysostosis with multiple hormone resistance	DIS6U70H	Definitive	Autosomal dominant	[1]
Pigmented nodular adrenocortical disease, primary, 1	DISQQ9QA	Strong	Autosomal dominant	[3]
Acrodysostosis	DISSV94Z	Supportive	Autosomal dominant	[1]
Carney complex	DISVL3IP	Supportive	Autosomal dominant	[4]
Familial atrial myxoma	DIS7K7LR	Supportive	Autosomal dominant	[5]
Primary pigmented nodular adrenocortical disease	DISXCNDR	Supportive	Autosomal dominant	[6]

4 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 cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the phosphorylation of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[15]
Mitotane	DMU1GX0	Approved	Mitotane decreases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[16]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[23]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[24]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A).	[18]

References

• [1] Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N Engl J Med. 2011 Jun 9;364(23):2218-26. doi: 10.1056/NEJMoa1012717.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab. 2002 Sep;87(9):4324-9. doi: 10.1210/jc.2002-020592.
• [4] Carney Complex. 2003 Feb 5 [updated 2023 Sep 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [5] Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000 Sep;26(1):89-92. doi: 10.1038/79238.
• [6] Primary pigmented nodular adrenocortical disease: the original 4 cases revisited after 30 years for follow-up, new investigations, and molecular genetic findings. Am J Surg Pathol. 2014 Sep;38(9):1266-73. doi: 10.1097/PAS.0000000000000220.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [13] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [14] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [15] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [16] The effect of mitotane on viability, steroidogenesis and gene expression in NCI295R adrenocortical cells. Mol Med Rep. 2013 Mar;7(3):893-900.
• [17] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [18] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [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] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] 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.
• [23] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [24] 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.