Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCEVJ9E)

• DOT Name: Mitogen-activated protein kinase 9 (MAPK9)
• Synonyms: MAP kinase 9; MAPK 9; EC 2.7.11.24; JNK-55; Stress-activated protein kinase 1a; SAPK1a; Stress-activated protein kinase JNK2; c-Jun N-terminal kinase 2
• Gene Name: MAPK9
• UniProt ID: MK09_HUMAN
• PDB ID: 3E7O; 3NPC; 7CML; 7N8T; 8ELC
• EC Number: 2.7.11.24
• Pfam ID: PF00069
• Sequence:
  MSDSKCDSQFYSVQVADSTFTVLKRYQQLKPIGSGAQGIVCAAFDTVLGINVAVKKLSRP
  FQNQTHAKRAYRELVLLKCVNHKNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIH
  MELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTACTNF
  MMTPYVVTRYYRAPEVILGMGYKENVDIWSVGCIMGELVKGCVIFQGTDHIDQWNKVIEQ
  LGTPSAEFMKKLQPTVRNYVENRPKYPGIKFEELFPDWIFPSESERDKIKTSQARDLLSK
  MLVIDPDKRISVDEALRHPYITVWYDPAEAEAPPPQIYDAQLEEREHAIEEWKELIYKEV
  MDWEERSKNGVVKDQPSDAAVSSNATPSQSSSINDISSMSTEQTLASDTDSSLDASTGPL
  EGCR
• Function: Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation 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 MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1-specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-BMAL1 heterodimer and plays a role in the regulation of the circadian clock. Phosphorylates POU5F1, which results in the inhibition of POU5F1's transcriptional activity and enhances its proteasomal degradation; MAPK9 isoforms display different binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, whereas beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it.
• 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

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Mitogen-activated protein kinase 9 (MAPK9) decreases the response to substance of Afimoxifene.	[60]

23 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 Mitogen-activated protein kinase 9 (MAPK9).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the activity of Mitogen-activated protein kinase 9 (MAPK9).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[12]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[16]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the activity of Mitogen-activated protein kinase 9 (MAPK9).	[18]
Melatonin	DMKWFBT	Approved	Melatonin increases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[20]
Resiniferatoxin	DMP62L5	Phase 2	Resiniferatoxin increases the activity of Mitogen-activated protein kinase 9 (MAPK9).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[33]
PMID28870136-Compound-49	DMTUC9E	Patented	PMID28870136-Compound-49 increases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[36]
LY293111	DM03FHA	Discontinued in Phase 2	LY293111 increases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[38]
Dioscin	DM5H2W9	Preclinical	Dioscin increases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[41]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitogen-activated protein kinase 9 (MAPK9).	[42]
2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One	DMDN12L	Investigative	2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One decreases the activity of Mitogen-activated protein kinase 9 (MAPK9).	[54]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cannabidiol	DM0659E	Approved	Cannabidiol increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[15]
Vinblastine	DM5TVS3	Approved	Vinblastine increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[17]
Colchicine	DM2POTE	Approved	Colchicine increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[17]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[19]
Mebendazole	DMO14SG	Approved	Mebendazole increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[21]
Sanguinarine	DMDINFS	Approved	Sanguinarine increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[22]
Sorbitol	DMAN0DE	Approved	Sorbitol increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[23]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[24]
Curcumin	DMQPH29	Phase 3	Curcumin increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[25]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[26]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[27]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[28]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[29]
Puerarin	DMJIMXH	Phase 2	Puerarin increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitogen-activated protein kinase 9 (MAPK9).	[31]
LY294002	DMY1AFS	Phase 1	LY294002 increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[32]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[34]
Flavonoid derivative 1	DMCQP0B	Patented	Flavonoid derivative 1 increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[35]
TDZD-8	DMG6Q45	Patented	TDZD-8 increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[37]
WIN-55212-2	DMACBIW	Terminated	WIN-55212-2 increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[40]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[43]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[44]
Paraquat	DMR8O3X	Investigative	Paraquat increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[45]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[46]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[47]
Manganese	DMKT129	Investigative	Manganese increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[48]
U0126	DM31OGF	Investigative	U0126 increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[32]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[49]
Kaempferol	DMHEMUB	Investigative	Kaempferol increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[50]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[51]
LICOAGROCHACONE A	DMWY0TN	Investigative	LICOAGROCHACONE A decreases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[19]
methylglyoxal	DMRC3OZ	Investigative	methylglyoxal increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[52]
NORCANTHARIDIN	DM9B6Y1	Investigative	NORCANTHARIDIN increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[53]
CHLORANIL	DMCHGF1	Investigative	CHLORANIL increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[55]
MANGOSTIN	DMYQGDV	Investigative	MANGOSTIN increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[56]
Buthionine sulfoximine	DMJ46CB	Investigative	Buthionine sulfoximine decreases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[57]
Sulfate	DMW0ZBF	Investigative	Sulfate affects the methylation of Mitogen-activated protein kinase 9 (MAPK9).	[58]
CANTHARIDIC_ACID	DME32XU	Investigative	CANTHARIDIC_ACID increases the phosphorylation of Mitogen-activated protein kinase 9 (MAPK9).	[59]

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