Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDAC6Z0)

• DOT Name: cAMP-dependent protein kinase catalytic subunit PRKX (PRKX)
• Synonyms: PrKX; Protein kinase X; Protein kinase X-linked; Serine/threonine-protein kinase PRKX; EC 2.7.11.1; Protein kinase PKX1
• Gene Name: PRKX
• Related Disease:
  Autosomal dominant polycystic kidney disease
  Coronary heart disease
  Renal carcinoma
  Renal cell carcinoma
• UniProt ID: PRKX_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MEAPGLAQAAAAESDSRKVAEETPDGAPALCPSPEALSPEPPVYSLQDFDTLATVGTGTF
  GRVHLVKEKTAKHFFALKVMSIPDVIRLKQEQHVHNEKSVLKEVSHPFLIRLFWTWHDER
  FLYMLMEYVPGGELFSYLRNRGRFSSTTGLFYSAEIICAIEYLHSKEIVYRDLKPENILL
  DRDGHIKLTDFGFAKKLVDRTWTLCGTPEYLAPEVIQSKGHGRAVDWWALGILIFEMLSG
  FPPFFDDNPFGIYQKILAGKIDFPRHLDFHVKDLIKKLLVVDRTRRLGNMKNGANDVKHH
  RWFRSVDWEAVPQRKLKPPIVPKIAGDGDTSNFETYPENDWDTAAPVPQKDLEIFKNF
• Function: Serine/threonine protein kinase regulated by and mediating cAMP signaling in cells. Acts through phosphorylation of downstream targets that may include CREB, SMAD6 and PKD1 and has multiple functions in cellular differentiation and epithelial morphogenesis. Regulates myeloid cell differentiation through SMAD6 phosphorylation. Involved in nephrogenesis by stimulating renal epithelial cell migration and tubulogenesis. Also involved in angiogenesis through stimulation of endothelial cell proliferation, migration and vascular-like structure formation.
• Tissue Specificity: Widely expressed (at protein level). Specifically expressed in blood by macrophages and granulocytes according to PubMed:9860982.
• Reactome Pathway:
  CREB1 phosphorylation through the activation of Adenylate Cyclase (R-HSA-442720)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  PKA-mediated phosphorylation of CREB (R-HSA-111931)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Genetic Variation	[1]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[2]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[3]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[3]

14 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 catalytic subunit PRKX (PRKX).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[11]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[12]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone increases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[13]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of cAMP-dependent protein kinase catalytic subunit PRKX (PRKX).	[17]

1 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 catalytic subunit PRKX (PRKX).	[14]

References

• [1] Protein kinase X (PRKX) can rescue the effects of polycystic kidney disease-1 gene (PKD1) deficiency.Biochim Biophys Acta. 2008 Jan;1782(1):1-9. doi: 10.1016/j.bbadis.2007.09.003. Epub 2007 Sep 29.
• [2] Screening hub genes in coronary artery disease based on integrated analysis.Cardiol J. 2018;25(3):403-411. doi: 10.5603/CJ.a2017.0106. Epub 2017 Oct 5.
• [3] PRKX, TTBK2 and RSK4 expression causes Sunitinib resistance in kidney carcinoma- and melanoma-cell lines.Int J Cancer. 2012 Jul 15;131(2):E45-55. doi: 10.1002/ijc.26486. Epub 2012 Feb 28.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [11] Glucocorticoids inhibit cell death in ovarian cancer and up-regulate caspase inhibitor cIAP2. Clin Cancer Res. 2005 Sep 1;11(17):6325-32. doi: 10.1158/1078-0432.CCR-05-0182.
• [12] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [13] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [14] 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.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.