Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTQBR95)

• DTT Name: Stress-activated protein kinase 2a (p38 alpha)
• Synonyms: SAPK2A; P38 mitogen activatedprotein kinase; P38 Mitogen-activatedprotein kinase alpha; Mitogen-activated protein kinase p38 alpha; Mitogen-activated protein kinase 14; MXI2; MAX-interacting protein 2; MAPK 14; MAP kinase p38alpha; MAP kinase p38 alpha; MAP kinase MXI2; MAP kinase 14; Cytokine suppressive anti-inflammatory drug-binding protein; Cytokine suppressive anti-inflammatory drug binding protein; CSPB1; CSBP2; CSBP1; CSBP; CSAID-binding protein; CSAID binding protein; CRK1
• Gene Name: MAPK14
• DTT Type: Clinical trial target; [1]
• Related Disease:
  Vitamin deficiency [ICD-11: 5B55-5B5F]
  Myocardial infarction [ICD-11: BA41-BA43]
  Coronary atherosclerosis [ICD-11: BA80]
  Rheumatoid arthritis [ICD-11: FA20]
• BioChemical Class: Kinase
• UniProt ID: MK14_HUMAN
• TTD ID: T65864
• EC Number: EC 2.7.11.24
• Sequence:
  MSQERPTFYRQELNKTIWEVPERYQNLSPVGSGAYGSVCAAFDTKTGLRVAVKKLSRPFQ
  SIIHAKRTYRELRLLKHMKHENVIGLLDVFTPARSLEEFNDVYLVTHLMGADLNNIVKCQ
  KLTDDHVQFLIYQILRGLKYIHSADIIHRDLKPSNLAVNEDCELKILDFGLARHTDDEMT
  GYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVG
  TPGAELLKKISSESARNYIQSLTQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAA
  QALAHAYFAQYHDPDDEPVADPYDQSFESRDLLIDEWKSLTYDEVISFVPPPLDQEEMES
• Function: MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'. Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Rap1 signaling pathway (hsa04015)
  FoxO signaling pathway (hsa04068)
  Sphingolipid signaling pathway (hsa04071)
  Adrenergic signaling in cardiomyocytes (hsa04261)
  VEGF signaling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Platelet activation (hsa04611)
  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)
  Leukocyte transendothelial migration (hsa04670)
  Neurotrophin signaling pathway (hsa04722)
  Retrograde endocannabinoid signaling (hsa04723)
  Dopaminergic synapse (hsa04728)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  GnRH signaling pathway (hsa04912)
  Progesterone-mediated oocyte maturation (hsa04914)
  Prolactin signaling pathway (hsa04917)
  Amyotrophic lateral sclerosis (ALS) (hsa05014)
  Epithelial cell signaling in Helicobacter pylori infection (hsa05120)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Leishmaniasis (hsa05140)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Influenza A (hsa05164)
  Epstein-Barr virus infection (hsa05169)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  p38MAPK events (R-HSA-171007)
  ERK/MAPK targets (R-HSA-198753)
  Activation of PPARGC1A (PGC-1alpha) by phosphorylation (R-HSA-2151209)
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  CDO in myogenesis (R-HSA-375170)
  DSCAM interactions (R-HSA-376172)
  ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)
  Platelet sensitization by LDL (R-HSA-432142)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  Activation of the AP-1 family of transcription factors (R-HSA-450341)
  KSRP (KHSRP) binds and destabilizes mRNA (R-HSA-450604)
  NOD1/2 Signaling Pathway (R-HSA-168638)
• BioCyc Pathway: MetaCyc:HS03507-MON

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ozagrel	DMIGKA1	Xerophthalmia	5B55.Y	Phase 4	[1]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Losmapimod	DMIL37Z	Acute coronary syndrome	BA41	Phase 3	[1]
VX-702	DMKJDR6	Coronary artery disease	BA80	Phase 2a	[2], [3]
Dilmapimod	DMBYJ92	Acute lung injury	NB32.3	Phase 2	[1]
VX-745	DMJAEG6	Alzheimer disease	8A20	Phase 2	[4], [5], [6]

6 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID25991433-Compound-A1	DM89LF0	N. A.	N. A.	Patented	[7]
PMID25991433-Compound-F2	DM37VIQ	N. A.	N. A.	Patented	[7]
PMID25991433-Compound-L1	DM2135Y	N. A.	N. A.	Patented	[7]
PMID25991433-Compound-L2	DM58UO9	N. A.	N. A.	Patented	[7]
PMID25991433-Compound-L3	DM3LWUR	N. A.	N. A.	Patented	[7]
PMID25991433-Compound-O2	DMTROIQ	N. A.	N. A.	Patented	[7]

8 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PAMAPIMOD	DM9SYUT	Rheumatoid arthritis	FA20	Discontinued in Phase 2	[8]
FR167653	DM69OR8	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 1	[9], [10]
R-1487	DM7WPI0	Rheumatoid arthritis	FA20	Discontinued in Phase 1	[11]
SB 235699	DMNH8XU	Psoriasis vulgaris	EA90	Discontinued in Phase 1	[4], [12]
SB-242235	DMKSFL0	Arthritis	FA20	Discontinued in Phase 1	[13]
SB 203580	DMAET6F	N. A.	N. A.	Terminated	[14], [15]
SB220025	DMSBUET	Arthritis	FA20	Terminated	[16]
SC-102	DM1MQ6Z	Solid tumour/cancer	2A00-2F9Z	Terminated	[17]

56 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(5-amino-1-phenyl-1H-pyrazol-4-yl)phenylmethanone	DMF0YJ3	Discovery agent	N.A.	Investigative	[18]
2-Chlorophenol	DM2E3X5	Discovery agent	N.A.	Investigative	[16]
3-(1-NAPHTHYLMETHOXY)PYRIDIN-2-AMINE	DMXMBEF	Discovery agent	N.A.	Investigative	[17]
3-(Benzyloxy)Pyridin-2-Amine	DM35VEI	Discovery agent	N.A.	Investigative	[16]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[19]
4-(2-Ethyl-4-m-tolyl-thiazol-5-yl)-pyridine	DMFJW2E	Discovery agent	N.A.	Investigative	[20]
4-PHENOXY-N-(PYRIDIN-2-YLMETHYL)BENZAMIDE	DMIPQTW	Discovery agent	N.A.	Investigative	[17]
4-Phenylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine	DMHANXD	Discovery agent	N.A.	Investigative	[21]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol	DMSKJ1X	Discovery agent	N.A.	Investigative	[22]
6-(4-Fluoro-phenylsulfanyl)-9H-purine	DM5JWEY	Discovery agent	N.A.	Investigative	[21]
6-Benzylsulfanyl-9H-purine	DMI7FNZ	Discovery agent	N.A.	Investigative	[21]
6-o-tolylquinazolin-2-amine	DM4TX9O	Discovery agent	N.A.	Investigative	[23]
6-Phenylsulfanyl-9H-purine	DMZ76NQ	Discovery agent	N.A.	Investigative	[21]
9-(4-Fluoro-benzyl)-6-phenylsulfanyl-9H-purine	DMW2NY9	Discovery agent	N.A.	Investigative	[21]
9-Benzyl-6-(4-fluoro-phenylsulfanyl)-9H-purine	DM8Q0D9	Discovery agent	N.A.	Investigative	[21]
9-Benzyl-6-phenylsulfanyl-9H-purine	DMNCL5G	Discovery agent	N.A.	Investigative	[21]
B-Octylglucoside	DMMO75G	Discovery agent	N.A.	Investigative	[16]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[24]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[24]
Dihydro-quinolinone	DM9UK6D	Discovery agent	N.A.	Investigative	[25]
DP-802	DMARTC2	Inflammation	1A00-CA43.1	Investigative	[26]
GSK-280	DM325YR	Inflammation	1A00-CA43.1	Investigative	[26]
GW-788388	DMIBUW5	Solid tumour/cancer	2A00-2F9Z	Investigative	[27]
IN-1130	DM3YJXF	Discovery agent	N.A.	Investigative	[28]
IN-1166	DMMS6D3	Discovery agent	N.A.	Investigative	[28]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[24]
KT-5720	DM9J50F	Discovery agent	N.A.	Investigative	[24]
L-779450	DM51B74	Discovery agent	N.A.	Investigative	[29]
ML-3163	DM3S5UC	Discovery agent	N.A.	Investigative	[30]
ML-3375	DMXJY6W	Discovery agent	N.A.	Investigative	[31]
ML-3403	DMTQWI8	Discovery agent	N.A.	Investigative	[31]
N-(3-(trifluoromethoxy)benzyl)-4-phenoxybenzamide	DM6UC8Y	Discovery agent	N.A.	Investigative	[32]
N-(3-(trifluoromethyl)benzyl)-4-phenoxybenzamide	DMSMRF9	Discovery agent	N.A.	Investigative	[32]
N-(4-(trifluoromethyl)benzyl)-4-phenoxybenzamide	DMZ0V8O	Discovery agent	N.A.	Investigative	[32]
N-(4-fluorobenzyl)-N-(pyridin-4-yl)-2-naphthamide	DMP1ICB	Discovery agent	N.A.	Investigative	[33]
N-(4-methyl-benzyl)-4-phenoxy-benzamide	DMZX2BH	Discovery agent	N.A.	Investigative	[32]
Oxindole 94	DMPFD6Y	Pain	MG30-MG3Z	Investigative	[34]
PD-0166326	DMD2CG9	Discovery agent	N.A.	Investigative	[35]
PD-0173956	DM8RW92	Discovery agent	N.A.	Investigative	[35]
PHA-666859	DMHQ6KT	Diabetic retinopathy	9B71.0	Investigative	[26]
Phenyl-(3-phenyl-1H-indazol-6-yl)-amine	DMDCTNU	Discovery agent	N.A.	Investigative	[36]
PMID22521646C12	DMYQDXO	Discovery agent	N.A.	Investigative	[37]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[24]
Ro-3201195	DM9GXYV	Discovery agent	N.A.	Investigative	[38]
Ro31-8220	DMDJLF0	Discovery agent	N.A.	Investigative	[24]
RWJ-68354	DMNLVRS	Discovery agent	N.A.	Investigative	[39]
SB-216995	DMOH9TA	Discovery agent	N.A.	Investigative	[25]
SB-218655	DMJKE4M	Discovery agent	N.A.	Investigative	[25]
SB-227931	DMO1WI8	Discovery agent	N.A.	Investigative	[40]
Small molecule 34	DMWJ70Q	Discovery agent	N.A.	Investigative	[16]
STAUROSPORINONE	DMU2H4K	Discovery agent	N.A.	Investigative	[24]
Talmapimod	DMMTSL2	Discovery agent	N.A.	Investigative	[41], [42]
Triazolopyridine	DM1F2K0	Discovery agent	N.A.	Investigative	[17]
Tyrphostin Ag-1478	DM87ZIH	Discovery agent	N.A.	Investigative	[43]
UCB-1277763	DMFUE43	Inflammation	1A00-CA43.1	Investigative	[26]
ZM-336372	DMD5JYQ	Discovery agent	N.A.	Investigative	[44]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Coronary artery disease	BA80-BA8Z	Peripheral blood	4.57E-01	-0.55	-0.55
Psoriasis	EA90	Skin	4.95E-14	0.48	1.09
Rheumatoid arthritis	FA20	Synovial tissue	7.98E-04	1.33	2.48
Chronic obstructive pulmonary disease	CA23	Lung tissue	7.60E-01	-0.01	-0.02
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	6.17E-03	-0.26	-0.49

References

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