Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT3IVG2)

• DTT Name: JNK2 messenger RNA (JNK2 mRNA)
• Synonyms: Stress-activated protein kinase 1a (mRNA); SAPK1a (mRNA); PRKM9 (mRNA); Mitogen-activated protein kinase 9 (mRNA); Mitogen-activated protein kinase 8-interacting protein 2 (mRNA); MAPK 9 (mRNA); MAP kinase 9 (mRNA); Jun-N-terminal kinase 2 (mRNA); JNK-interacting protein 2 (mRNA); JNK-55 (mRNA); JNK MAP kinase scaffold protein 2 (mRNA); JIP-2 (mRNA); Islet-brain-2 (mRNA); IB-2 (mRNA); C-jun-amino-terminal kinase interacting protein 2 (mRNA); C-Jun N-terminal kinase 2 (mRNA)
• Gene Name: MAPK9
• DTT Type: Literature-reported target; [1]
• BioChemical Class: mRNA target
• UniProt ID: MK09_HUMAN
• TTD ID: T06037
• EC Number: EC 2.7.11.24
• Sequence:
  MSDSKCDSQFYSVQVADSTFTVLKRYQQLKPIGSGAQGIVCAAFDTVLGINVAVKKLSRP
  FQNQTHAKRAYRELVLLKCVNHKNIISLLNVFTPQKTLEEFQDVYLVMELMDANLCQVIH
  MELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTACTNF
  MMTPYVVTRYYRAPEVILGMGYKENVDIWSVGCIMGELVKGCVIFQGTDHIDQWNKVIEQ
  LGTPSAEFMKKLQPTVRNYVENRPKYPGIKFEELFPDWIFPSESERDKIKTSQARDLLSK
  MLVIDPDKRISVDEALRHPYITVWYDPAEAEAPPPQIYDAQLEEREHAIEEWKELIYKEV
  MDWEERSKNGVVKDQPSDAAVSSNATPSQSSSINDISSMSTEQTLASDTDSSLDASTGPL
  EGCR
• Function: Extracellular stimuli such as proinflammatory 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-ARNTL/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 proteosomal degradation. Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  ErbB signaling pathway (hsa04012)
  Ras signaling pathway (hsa04014)
  cAMP signaling pathway (hsa04024)
  FoxO signaling pathway (hsa04068)
  Sphingolipid signaling pathway (hsa04071)
  Protein processing in endoplasmic reticulum (hsa04141)
  Wnt signaling pathway (hsa04310)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Toll-like receptor signaling pathway (hsa04620)
  NOD-like receptor signaling pathway (hsa04621)
  RIG-I-like receptor signaling pathway (hsa04622)
  T cell receptor signaling pathway (hsa04660)
  Fc epsilon RI signaling pathway (hsa04664)
  TNF signaling pathway (hsa04668)
  Neurotrophin signaling pathway (hsa04722)
  Retrograde endocannabinoid signaling (hsa04723)
  Dopaminergic synapse (hsa04728)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin signaling pathway (hsa04910)
  GnRH signaling pathway (hsa04912)
  Progesterone-mediated oocyte maturation (hsa04914)
  Prolactin signaling pathway (hsa04917)
  Adipocytokine signaling pathway (hsa04920)
  Type II diabetes mellitus (hsa04930)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Epithelial cell signaling in Helicobacter pylori infection (hsa05120)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Influenza A (hsa05164)
  Herpes simplex infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
  Choline metabolism in cancer (hsa05231)
• 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 DTT

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AC1LG8KT	DMFKV97	Discovery agent	N.A.	Investigative	[1]
Aminopyridine deriv. 2	DM94KQP	Discovery agent	N.A.	Investigative	[2]
AS-601245	DMQ95EB	Discovery agent	N.A.	Investigative	[3]
IN-1166	DMMS6D3	Discovery agent	N.A.	Investigative	[4]
ISIS 18078	DMHZPJ0	Solid tumour/cancer	2A00-2F9Z	Investigative	[5]
JNK-IN-8	DMLWYJB	Discovery agent	N.A.	Investigative	[6]
N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)acetamide	DMY1FMG	Discovery agent	N.A.	Investigative	[2]
N-(4-amino-5-cyano-6-phenylpyridin-2-yl)acetamide	DMUFVM6	Discovery agent	N.A.	Investigative	[2]
N-(4-amino-6-butoxy-5-cyanopyridin-2-yl)acetamide	DMSAD87	Discovery agent	N.A.	Investigative	[2]

References

• [1] N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3. Bioorg Med Chem Lett. 2007 Mar 1;17(5):1296-301.
• [2] Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity. J Med Chem. 2006 Jun 15;49(12):3563-80.
• [3] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.
• [4] Synthesis and biological evaluation of 4(5)-(6-alkylpyridin-2-yl)imidazoles as transforming growth factor-beta type 1 receptor kinase inhibitors. J Med Chem. 2007 Jun 28;50(13):3143-7.
• [5] US patent application no. 7,425,545, Modulation of C-reactive protein expression.
• [6] Discovery of potent and selective covalent inhibitors of JNK. Chem Biol. 2012 Jan 27;19(1):140-54.