Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYM6437)

• DOT Name: Inactive serine/threonine-protein kinase 19 (STK19)
• Synonyms: Protein G11; Protein RP1
• Gene Name: STK19
• Related Disease:
  Age-related macular degeneration
  Cutaneous melanoma
  Cutaneous squamous cell carcinoma
  Lung adenocarcinoma
  Major depressive disorder
  Membranous glomerulonephritis
  Multiple sclerosis
  Myasthenia gravis
  Neovascular age-related macular degeneration
  Pemphigus vulgaris
  Rheumatoid arthritis
  Sarcoidosis
  Schizophrenia
  Systemic sclerosis
  Type-1 diabetes
  Lung cancer
  Melanoma
  Systemic lupus erythematosus
• UniProt ID: STK19_HUMAN
• PDB ID: 7XRB
• Pfam ID: PF10494
• Sequence:
  MSWKRHHLIPETFGVKRRRKRGPVESDPLRGEPGSARAAVSELMQLFPRGLFEDALPPIV
  LRSQVYSLVPDRTVADRQLKELQEQGEIRIVQLGFDLDAHGIIFTEDYRTRVLKACDGRP
  YAGAVQKFLASVLPACGDLSFQQDQMTQTFGFRDSEITHLVNAGVLTVRDAGSWWLAVPG
  AGRFIKYFVKGRQAVLSMVRKAKYRELLLSELLGRRAPVVVRLGLTYHVHDLIGAQLVDC
  ISTTSGTLLRLPET
• Function: [Isoform 1]: Inactive serine/threonine-protein kinase (Probable). May control NRAS activity via an associated kinase (Probable); [Isoform 3]: Inactive serine/threonine-protein kinase.
• Tissue Specificity: Monocytes, hepatocytes, epithelial cells, T- and B-lymphocytes.

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[1]
Cutaneous melanoma	DIS3MMH9	Strong	Genetic Variation	[2]
Cutaneous squamous cell carcinoma	DIS3LXUG	Strong	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[3]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Membranous glomerulonephritis	DISFSUKQ	Strong	Genetic Variation	[5]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[6]
Myasthenia gravis	DISELRCI	Strong	Genetic Variation	[7]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[1]
Pemphigus vulgaris	DISENR62	Strong	Genetic Variation	[8]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[9]
Sarcoidosis	DISE5B8Z	Strong	Genetic Variation	[10]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[11]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[12]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[13]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[14]
Melanoma	DIS1RRCY	Limited	Biomarker	[15]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Inactive serine/threonine-protein kinase 19 (STK19).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Inactive serine/threonine-protein kinase 19 (STK19).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Inactive serine/threonine-protein kinase 19 (STK19).	[19]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Inactive serine/threonine-protein kinase 19 (STK19).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Inactive serine/threonine-protein kinase 19 (STK19).	[22]

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 affects the methylation of Inactive serine/threonine-protein kinase 19 (STK19).	[21]

References

• [1] A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet. 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448. Epub 2015 Dec 21.
• [2] Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.
• [3] A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma.Am J Hum Genet. 2009 Nov;85(5):679-91. doi: 10.1016/j.ajhg.2009.09.012. Epub 2009 Oct 15.
• [4] Bivariate genome-wide association analyses of the broad depression phenotype combined with major depressive disorder, bipolar disorder or schizophrenia reveal eight novel genetic loci for depression.Mol Psychiatry. 2020 Jul;25(7):1420-1429. doi: 10.1038/s41380-018-0336-6. Epub 2019 Jan 9.
• [5] Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy.N Engl J Med. 2011 Feb 17;364(7):616-26. doi: 10.1056/NEJMoa1009742.
• [6] Evidence for VAV2 and ZNF433 as susceptibility genes for multiple sclerosis.J Neuroimmunol. 2010 Oct 8;227(1-2):162-6. doi: 10.1016/j.jneuroim.2010.06.003. Epub 2010 Jul 2.
• [7] Risk for myasthenia gravis maps to a (151) ProAla change in TNIP1 and to human leukocyte antigen-B*08.Ann Neurol. 2012 Dec;72(6):927-35. doi: 10.1002/ana.23691. Epub 2012 Oct 10.
• [8] Population-specific association between a polymorphic variant in ST18, encoding a pro-apoptotic molecule, and pemphigus vulgaris.J Invest Dermatol. 2012 Jul;132(7):1798-805. doi: 10.1038/jid.2012.46. Epub 2012 Mar 22.
• [9] A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis.Ann Rheum Dis. 2011 Feb;70(2):259-65. doi: 10.1136/ard.2009.126821. Epub 2010 Dec 14.
• [10] High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences.Am J Respir Crit Care Med. 2016 May 1;193(9):1008-22. doi: 10.1164/rccm.201507-1372OC.
• [11] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [12] Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus.Nat Genet. 2010 May;42(5):426-9. doi: 10.1038/ng.565. Epub 2010 Apr 11.
• [13] A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.Nature. 2007 Aug 2;448(7153):591-4. doi: 10.1038/nature06010. Epub 2007 Jul 15.
• [14] Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.Hum Mol Genet. 2012 Nov 15;21(22):4980-95. doi: 10.1093/hmg/dds334. Epub 2012 Aug 16.
• [15] Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis.Cell. 2019 Feb 21;176(5):1113-1127.e16. doi: 10.1016/j.cell.2019.01.002. Epub 2019 Jan 31.
• [16] GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.Genes Immun. 2014 Sep;15(6):347-54. doi: 10.1038/gene.2014.23. Epub 2014 May 29.
• [17] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [18] 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.
• [19] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [20] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [21] 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.
• [22] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.