Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSP1WLK)

• DOT Name: PX domain-containing protein kinase-like protein (PXK)
• Synonyms: Modulator of Na,K-ATPase; MONaKA
• Gene Name: PXK
• Related Disease:
  Systemic sclerosis
  Autoimmune disease
  IgA nephropathy
  Multiple sclerosis
  Rheumatoid arthritis
• UniProt ID: PXK_HUMAN
• Pfam ID: PF00787 ; PF02205
• Sequence:
  MAFMEKPPAGKVLLDDTVPLTAAIEASQSLQSHTEYIIRVQRGISVENSWQIVRRYSDFD
  LLNNSLQIAGLSLPLPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFLD
  PNNYSANYTEIALQQVSMFFRSEPKWEVVEPLKDIGWRIRKKYFLMKIKNQPKERLVLSW
  ADLGPDKYLSDKDFQCLIKLLPSCLHPYIYRVTFATANESSALLIRMFNEKGTLKDLIYK
  AKPKDPFLKKYCNPKKIQGLELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGDT
  CRLLDLENSLLGLPSFYRSYFSQFRKINTLESVDVHCFGHLLYEMTYGRPPDSVPVDSFP
  PAPSMAVVAVLESTLSCEACKNGMPTISRLLQMPLFSDVLLTTSEKPQFKIPTKLKEALR
  IAKECIEKRLIEEQKQIHQHRRLTRAQSHHGSEEERKKRKILARKKSKRSALENSEEHSA
  KYSNSNNSAGSGASSPLTSPSSPTPPSTSGISALPPPPPPPPPPAAPLPPASTEAPAQLS
  SQAVNGMSRGALLSSIQNFQKGTLRKAKTCDHSAPKIG
• Function: Binds to and modulates brain Na,K-ATPase subunits ATP1B1 and ATP1B3 and may thereby participate in the regulation of electrical excitability and synaptic transmission. May not display kinase activity.
• Tissue Specificity: Widely expressed in all tissues examined except in heart. Isoform 1 is expressed in high levels in the brain, skeletal muscle, spleen and testis. Isoform 7 expression has yet to be demonstrated.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Systemic sclerosis	DISF44L6	Definitive	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[2]
IgA nephropathy	DISZ8MTK	Strong	Biomarker	[3]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[5]

17 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 PX domain-containing protein kinase-like protein (PXK).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of PX domain-containing protein kinase-like protein (PXK).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of PX domain-containing protein kinase-like protein (PXK).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PX domain-containing protein kinase-like protein (PXK).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of PX domain-containing protein kinase-like protein (PXK).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of PX domain-containing protein kinase-like protein (PXK).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of PX domain-containing protein kinase-like protein (PXK).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of PX domain-containing protein kinase-like protein (PXK).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of PX domain-containing protein kinase-like protein (PXK).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of PX domain-containing protein kinase-like protein (PXK).	[15]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of PX domain-containing protein kinase-like protein (PXK).	[16]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of PX domain-containing protein kinase-like protein (PXK).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of PX domain-containing protein kinase-like protein (PXK).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of PX domain-containing protein kinase-like protein (PXK).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of PX domain-containing protein kinase-like protein (PXK).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of PX domain-containing protein kinase-like protein (PXK).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of PX domain-containing protein kinase-like protein (PXK).	[21]

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 PX domain-containing protein kinase-like protein (PXK).	[19]

References

• [1] GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.Nat Commun. 2019 Oct 31;10(1):4955. doi: 10.1038/s41467-019-12760-y.
• [2] A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci.Hum Mol Genet. 2013 Oct 1;22(19):4021-9. doi: 10.1093/hmg/ddt248. Epub 2013 Jun 4.
• [3] Association of systemic lupus erythematosus susceptibility genes with IgA nephropathy in a Chinese cohort.Clin J Am Soc Nephrol. 2014 Apr;9(4):788-97. doi: 10.2215/CJN.01860213. Epub 2014 Jan 23.
• [4] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [5] Detecting novel micro RNAs in rheumatoid arthritis with gene-based association testing.Clin Exp Rheumatol. 2017 Jul-Aug;35(4):586-592. Epub 2017 Jan 27.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] 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.
• [10] 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.
• [11] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [12] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [17] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] 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.
• [21] 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.