Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC46VX1)

• DOT Name: Mitogen-activated protein kinase 10 (MAPK10)
• Synonyms: MAP kinase 10; MAPK 10; EC 2.7.11.24; MAP kinase p49 3F12; Stress-activated protein kinase 1b; SAPK1b; Stress-activated protein kinase JNK3; c-Jun N-terminal kinase 3
• Gene Name: MAPK10
• Related Disease: LennoxGastaut syndrome
• UniProt ID: MK10_HUMAN
• PDB ID: 1JNK ; 1PMN ; 1PMU ; 1PMV ; 2B1P ; 2EXC ; 2O0U ; 2O2U ; 2OK1 ; 2P33 ; 2R9S ; 2WAJ ; 2ZDT ; 2ZDU ; 3CGF ; 3CGO ; 3DA6 ; 3FI2 ; 3FI3 ; 3FV8 ; 3G90 ; 3G9L ; 3G9N ; 3KVX ; 3OXI ; 3OY1 ; 3PTG ; 3RTP ; 3TTI ; 3TTJ ; 3V6R ; 3V6S ; 4H36 ; 4H39 ; 4H3B ; 4KKE ; 4KKG ; 4KKH ; 4U79 ; 4W4V ; 4W4W ; 4W4X ; 4W4Y ; 4WHZ ; 4X21 ; 4Y46 ; 4Y5H ; 4Z9L ; 6EKD ; 6EMH ; 6EQ9 ; 7KSI ; 7KSJ ; 7KSK ; 7ORE ; 7ORF ; 7S1N ; 7YL1 ; 8BZP ; 8ENJ ; 8WGF
• EC Number: 2.7.11.24
• Pfam ID: PF00069
• Sequence:
  MSLHFLYYCSEPTLDVKIAFCQGFDKQVDVSYIAKHYNMSKSKVDNQFYSVEVGDSTFTV
  LKRYQNLKPIGSGAQGIVCAAYDAVLDRNVAIKKLSRPFQNQTHAKRAYRELVLMKCVNH
  KNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIQMELDHERMSYLLYQMLCGIKHL
  HSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSFMMTPYVVTRYYRAPEVILGMGY
  KENVDIWSVGCIMGEMVRHKILFPGRDYIDQWNKVIEQLGTPCPEFMKKLQPTVRNYVEN
  RPKYAGLTFPKLFPDSLFPADSEHNKLKASQARDLLSKMLVIDPAKRISVDDALQHPYIN
  VWYDPAEVEAPPPQIYDKQLDEREHTIEEWKELIYKEVMNSEEKTKNGVVKGQPSPSGAA
  VNSSESLPPSSSVNDISSMSTDQTLASDTDSSLEASAGPLGCCR
• Function: Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as pro-inflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the amyloid-beta precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-BMAL1 heterodimer and plays a role in the photic regulation of the circadian clock. Phosphorylates JUND and this phosphorylation is inhibited in the presence of MEN1.
• Tissue Specificity: Specific to a subset of neurons in the nervous system. Present in the hippocampus and areas, cerebellum, striatum, brain stem, and weakly in the spinal cord. Very weak expression in testis and kidney.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  cAMP sig.ling pathway (hsa04024)
  FoxO sig.ling pathway (hsa04068)
  Sphingolipid sig.ling pathway (hsa04071)
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  Protein processing in endoplasmic reticulum (hsa04141)
  Apoptosis (hsa04210)
  Apoptosis - multiple species (hsa04215)
  Necroptosis (hsa04217)
  Wnt sig.ling pathway (hsa04310)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Tight junction (hsa04530)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  C-type lectin receptor sig.ling pathway (hsa04625)
  IL-17 sig.ling pathway (hsa04657)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  Fc epsilon RI sig.ling pathway (hsa04664)
  TNF sig.ling pathway (hsa04668)
  Neurotrophin sig.ling pathway (hsa04722)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Dopaminergic sy.pse (hsa04728)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin sig.ling pathway (hsa04910)
  GnRH sig.ling pathway (hsa04912)
  Progesterone-mediated oocyte maturation (hsa04914)
  Prolactin sig.ling pathway (hsa04917)
  Adipocytokine sig.ling pathway (hsa04920)
  Relaxin sig.ling pathway (hsa04926)
  Type II diabetes mellitus (hsa04930)
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alcoholic liver disease (hsa04936)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Yersinia infection (hsa05135)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
  Choline metabolism in cancer (hsa05231)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  FCERI mediated MAPK activation (R-HSA-2871796)
  JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 (R-HSA-450321)
  Activation of the AP-1 family of transcription factors (R-HSA-450341)
  Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
LennoxGastaut syndrome	DISOTGO5	Limited	Autosomal dominant	[1]

5 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Mitogen-activated protein kinase 10 (MAPK10).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitogen-activated protein kinase 10 (MAPK10).	[13]
Flavonoid derivative 1	DMCQP0B	Patented	Flavonoid derivative 1 increases the phosphorylation of Mitogen-activated protein kinase 10 (MAPK10).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Mitogen-activated protein kinase 10 (MAPK10).	[17]
Sulfate	DMW0ZBF	Investigative	Sulfate affects the methylation of Mitogen-activated protein kinase 10 (MAPK10).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[4]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[5]
Menadione	DMSJDTY	Approved	Menadione decreases the activity of Mitogen-activated protein kinase 10 (MAPK10).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[7]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[8]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[9]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[10]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[11]
Melatonin	DMKWFBT	Approved	Melatonin increases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[12]
Sorbitol	DMAN0DE	Approved	Sorbitol increases the activity of Mitogen-activated protein kinase 10 (MAPK10).	[6]
Dicumarol	DMFQCB1	Approved	Dicumarol decreases the activity of Mitogen-activated protein kinase 10 (MAPK10).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[7]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[18]
L-Serine	DM6WPIS	Investigative	L-Serine decreases the expression of Mitogen-activated protein kinase 10 (MAPK10).	[19]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [3] 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.
• [4] 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.
• [5] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [6] Quinone reductase inhibitors block SAPK/JNK and NFkappaB pathways and potentiate apoptosis. J Biol Chem. 1999 Oct 29;274(44):31150-4. doi: 10.1074/jbc.274.44.31150.
• [7] 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.
• [8] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [9] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [10] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [11] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [12] Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. J Pineal Res. 2008 Nov;45(4):532-40. doi: 10.1111/j.1600-079X.2008.00641.x.
• [13] 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.
• [14] The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016 Feb 18;35(7):833-45.
• [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] Luteolin induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells. Toxicol In Vitro. 2011 Oct;25(7):1385-91. doi: 10.1016/j.tiv.2011.05.009. Epub 2011 May 13.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [19] Mechanisms of L-Serine Neuroprotection in vitro Include ER Proteostasis Regulation. Neurotox Res. 2018 Jan;33(1):123-132. doi: 10.1007/s12640-017-9829-3. Epub 2017 Nov 2.
• [20] Short-term airborne particulate matter exposure alters the epigenetic landscape of human genes associated with the mitogen-activated protein kinase network: a cross-sectional study. Environ Health. 2014 Nov 13;13:94. doi: 10.1186/1476-069X-13-94.