Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT0K6EO)

• DTT Name: Stress-activated protein kinase JNK1 (JNK1)
• Synonyms: Stress-activated protein kinase 1c; SAPK1c; PRKM8; Mitogen-activated protein kinase 8; MAPK 8; MAP kinase 8; JNK-46; C-Jun N-terminal kinase 1
• Gene Name: MAPK8
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: MK08_HUMAN
• TTD ID: T40097
• EC Number: EC 2.7.11.24
• Sequence:
  MSRSKRDNNFYSVEIGDSTFTVLKRYQNLKPIGSGAQGIVCAAYDAILERNVAIKKLSRP
  FQNQTHAKRAYRELVLMKCVNHKNIIGLLNVFTPQKSLEEFQDVYIVMELMDANLCQVIQ
  MELDHERMSYLLYQMLCGIKHLHSAGIIHRDLKPSNIVVKSDCTLKILDFGLARTAGTSF
  MMTPYVVTRYYRAPEVILGMGYKENVDLWSVGCIMGEMVCHKILFPGRDYIDQWNKVIEQ
  LGTPCPEFMKKLQPTVRTYVENRPKYAGYSFEKLFPDVLFPADSEHNKLKASQARDLLSK
  MLVIDASKRISVDEALQHPYINVWYDPSEAEAPPPKIPDKQLDEREHTIEEWKELIYKEV
  MDLEERTKNGVIRGQPSPLGAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDSSLEAAA
  GPLGCCR
• 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 MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock. Phosphorylates the heat shock transcription factor HSF1, suppressing HSF1-induced transcriptional activity. 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)
  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)
  HTLV-I infection (hsa05166)
  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:
  NRIF signals cell death from the nucleus (R-HSA-205043)
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  FCERI mediated MAPK activation (R-HSA-2871796)
  DSCAM interactions (R-HSA-376172)
  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)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NKP-1339	DM5AWK1	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]

43 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
7-azaindole derivative 1	DMQL5B7	N. A.	N. A.	Patented	[3]
7-azaindole derivative 2	DMZRM2Q	N. A.	N. A.	Patented	[3]
7-azaindole derivative 3	DMQ7BV4	N. A.	N. A.	Patented	[3]
7-azaindole derivative 5	DMV3H98	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-A1	DM89LF0	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-A10	DM39NBT	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-A11	DMD59C2	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-A2	DMX7MHC	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-A3	DMJ1X53	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-A5	DM5YD1K	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-A6	DMFSB9Y	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-A7	DM2ISDH	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-A8	DMHG4WD	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-A9	DMPYCIM	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-D1	DMXSK8Y	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-D2	DMLWSNA	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-E1	DMKWFVP	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-E2	DM8YR1V	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-E3	DM62XNE	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-E4	DM1VHYX	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-E5	DM2ZCTW	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-Eb	DM536JN	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-F2	DM37VIQ	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-G1	DMHS3ZW	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-G2	DMU3XBH	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-G4	DMACWQY	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-G5	DMRJ1KY	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-H1	DM0Q37R	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-H2	DMZ9BTN	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-H3	DMQKLX0	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-J2	DMZSOCK	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-J3	DM17P3F	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-J5	DMU75ZX	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-K1	DMLT8PA	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-K2	DMBS4LE	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-L1	DM2135Y	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-N1	DMN27QB	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-N3	DMLHC5V	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-O3	DMVOWS5	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-P1	DMD8AX6	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-P4	DMVF1D6	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-P5	DM6FCS9	N. A.	N. A.	Patented	[3]
PMID25991433-Compound-P6	DMNDVC9	N. A.	N. A.	Patented	[3]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
COR-D	DMLXMCB	T-cell leukaemia	2A90	Preclinical	[4]

25 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One	DMDN12L	Discovery agent	N.A.	Investigative	[5]
2-(2-(butylamino)pyrimidin-4-ylamino)benzoic acid	DMZA8M7	Discovery agent	N.A.	Investigative	[6]
2-(2-(pentyloxy)pyrimidin-4-ylamino)benzoic acid	DM4KS27	Discovery agent	N.A.	Investigative	[6]
2-(2-(phenylamino)pyrimidin-4-ylamino)benzamide	DM5GAOZ	Discovery agent	N.A.	Investigative	[6]
2-(2-butoxypyrimidin-4-ylamino)benzoic acid	DMLTU3J	Discovery agent	N.A.	Investigative	[6]
2-(2-phenoxypyrimidin-4-ylamino)benzoic acid	DME0HPA	Discovery agent	N.A.	Investigative	[6]
2-(2-propoxypyrimidin-4-ylamino)benzoic acid	DMGVCKZ	Discovery agent	N.A.	Investigative	[6]
2-(2-sec-butoxypyrimidin-4-ylamino)benzoic acid	DMB4W68	Discovery agent	N.A.	Investigative	[6]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[7]
Aminopyridine deriv. 2	DM94KQP	Discovery agent	N.A.	Investigative	[8]
AS-601245	DMQ95EB	Discovery agent	N.A.	Investigative	[9]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[1]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[1]
JNK-IN-8	DMLWYJB	Discovery agent	N.A.	Investigative	[10]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[1]
KT-5720	DM9J50F	Discovery agent	N.A.	Investigative	[1]
N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)acetamide	DMY1FMG	Discovery agent	N.A.	Investigative	[11]
N-(4-amino-5-cyano-6-phenylpyridin-2-yl)acetamide	DMUFVM6	Discovery agent	N.A.	Investigative	[8]
N-(4-amino-6-butoxy-5-cyanopyridin-2-yl)acetamide	DMSAD87	Discovery agent	N.A.	Investigative	[8]
N-(6-ethoxypyridin-2-yl)acetamide	DM90KGB	Discovery agent	N.A.	Investigative	[8]
NM-PP1	DMS8H5Q	Discovery agent	N.A.	Investigative	[9]
Phylomers	DMU30IO	Brain injury	NA07.Z	Investigative	[2]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[1]
Ro31-8220	DMDJLF0	Discovery agent	N.A.	Investigative	[1]
STAUROSPORINONE	DMU2H4K	Discovery agent	N.A.	Investigative	[1]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	1.48E-07	1.2	2.27

References

• [1] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1496).
• [3] c-Jun N-terminal kinase inhibitors: a patent review (2010 - 2014).Expert Opin Ther Pat. 2015;25(8):849-72.
• [4] Corchorusin-D directed apoptosis of K562 cells occurs through activation of mitochondrial and death receptor pathways and suppression of AKT/PKB pathway. Cell Physiol Biochem. 2012;30(4):915-26.
• [5] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [6] Discovery of a new class of 4-anilinopyrimidines as potent c-Jun N-terminal kinase inhibitors: Synthesis and SAR studies. Bioorg Med Chem Lett. 2007 Feb 1;17(3):668-72.
• [7] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.
• [8] 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.
• [9] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.
• [10] Discovery of potent and selective covalent inhibitors of JNK. Chem Biol. 2012 Jan 27;19(1):140-54.
• [11] Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors. J Med Chem. 2006 Jul 27;49(15):4455-8.