Target General Infomation
Target ID
T79798
Former ID
TTDC00044
Target Name
MAP kinase p38
Gene Name
MAPK12
Synonyms
ERK-6; ERK5; ERK6; Extracellular signal-regulated kinase 6; MAP kinase p38 gamma; Mitogen-activated proteinkinase 12; Mitogen-activated proteinkinase p38 gamma; SAPK3; Stress-activated protein kinase 3; MAPK12
Target Type
Clinical Trial
Disease Diabetic nephropathy [ICD9: 250.4; ICD10: E11.21]
Inflammatory bowel disease [ICD9: 555, 556; ICD10: K50, K51]
Inflammatory bowel disease; Rheumatoid arthritis; Cardiovascular disorders; Psoriasis [ICD9: 390-459, 555, 556, 696, 710-719, 714; ICD10: I00-I99, K50, K51, L40, M00-M25, M05-M06]
Osteoarthritis; Pain [ICD9: 338, 715,780; ICD10: M15-M19, M47, R52, G89]
Rheumatoid arthritis; Myelodysplastic syndrome [ICD9:710-719, 714, 238.7; ICD10: M05-M06, D46]
Function
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 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 such as ELK1 and ATF2. 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 such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma- radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.
BioChemical Class
Kinase
Target Validation
T79798
UniProt ID
EC Number
EC 2.7.11.24
Sequence
MSSPPPARSGFYRQEVTKTAWEVRAVYRDLQPVGSGAYGAVCSAVDGRTGAKVAIKKLYR
PFQSELFAKRAYRELRLLKHMRHENVIGLLDVFTPDETLDDFTDFYLVMPFMGTDLGKLM
KHEKLGEDRIQFLVYQMLKGLRYIHAAGIIHRDLKPGNLAVNEDCELKILDFGLARQADS
EMTGYVVTRWYRAPEVILNWMRYTQTVDIWSVGCIMAEMITGKTLFKGSDHLDQLKEIMK
VTGTPPAEFVQRLQSDEAKNYMKGLPELEKKDFASILTNASPLAVNLLEKMLVLDAEQRV
TAGEALAHPYFESLHDTEDEPQVQKYDDSFDDVDRTLDEWKRVTYKEVLSFKPPRQLGAR
VSKETPL
Drugs and Mode of Action
Drug(s) ARRY-797 Drug Info Phase 2 Osteoarthritis; Pain [547810]
CI-1040 Drug Info Phase 2 Discovery agent [521505], [541019]
VX-745 Drug Info Phase 2 Rheumatoid arthritis; Myelodysplastic syndrome [525164], [541057], [544340]
SMP-534 Drug Info Preclinical Diabetic nephropathy [536836]
BIRB 796 Drug Info Discontinued in Phase 2 Inflammatory bowel disease [541011], [547541]
KC706 Drug Info Discontinued in Phase 2 Inflammatory bowel disease; Rheumatoid arthritis; Cardiovascular disorders; Psoriasis [548224]
Inhibitor 4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole Drug Info [527308]
ARRY-797 Drug Info [550225]
BIRB 796 Drug Info [536977], [537039]
BISINDOLYLMALEIMIDE IX Drug Info [525872]
CI-1040 Drug Info [525872]
GF-109203 Drug Info [525872]
KC706 Drug Info [549786]
KN-62 Drug Info [525872]
KT-5720 Drug Info [525872]
ML-3163 Drug Info [526355]
ML-3375 Drug Info [526668]
ML-3403 Drug Info [526668]
Phosphoaminophosphonic Acid-Adenylate Ester Drug Info [551374]
Phosphonothreonine Drug Info [551393]
RO-316233 Drug Info [525872]
RWJ-68354 Drug Info [526530]
SMP-534 Drug Info [536836]
STAUROSPORINONE Drug Info [525872]
VK-19911 Drug Info [526904]
VX-745 Drug Info [536458], [536961]
Pathways
KEGG Pathway MAPK signaling pathway
Rap1 signaling pathway
FoxO signaling pathway
Sphingolipid signaling pathway
Oocyte meiosis
Adrenergic signaling in cardiomyocytes
VEGF signaling pathway
Osteoclast differentiation
Signaling pathways regulating pluripotency of stem cells
Platelet activation
Toll-like receptor signaling pathway
NOD-like receptor signaling pathway
RIG-I-like receptor signaling pathway
T cell receptor signaling pathway
Fc epsilon RI signaling pathway
TNF signaling pathway
Leukocyte transendothelial migration
Neurotrophin signaling pathway
Retrograde endocannabinoid signaling
Dopaminergic synapse
Inflammatory mediator regulation of TRP channels
GnRH signaling pathway
Progesterone-mediated oocyte maturation
Prolactin signaling pathway
Amyotrophic lateral sclerosis (ALS)
Epithelial cell signaling in Helicobacter pylori infection
Shigellosis
Salmonella infection
Pertussis
Leishmaniasis
Chagas disease (American trypanosomiasis)
Toxoplasmosis
Tuberculosis
Hepatitis C
Influenza A
Epstein-Barr virus infection
Proteoglycans in cancer
NetPath Pathway TCR Signaling Pathway
PANTHER Pathway Alzheimer disease-amyloid secretase pathway
B cell activation
EGF receptor signaling pathway
FGF signaling pathway
Interferon-gamma signaling pathway
Oxidative stress response
Parkinson disease
TGF-beta signaling pathway
Ras Pathway
p53 pathway feedback loops 2
p38 MAPK pathway
Pathway Interaction Database RhoA signaling pathway
Signaling mediated by p38-gamma and p38-delta
Reactome NOD1/2 Signaling Pathway
p38MAPK events
Activation of PPARGC1A (PGC-1alpha) by phosphorylation
CDO in myogenesis
DSCAM interactions
VEGFA-VEGFR2 Pathway
WikiPathways Toll-like receptor signaling pathway
Insulin Signaling
MAPK Cascade
MAPK Signaling Pathway
Nanoparticle-mediated activation of receptor signaling
Signal Transduction of S1P Receptor
Parkinsons Disease Pathway
miR-targeted genes in muscle cell - TarBase
miR-targeted genes in lymphocytes - TarBase
NGF signalling via TRKA from the plasma membrane
Myogenesis
Integrin-mediated Cell Adhesion
DSCAM interactions
Regulation of toll-like receptor signaling pathway
References
Ref 521505ClinicalTrials.gov (NCT00033384) CI-1040 in Treating Patients With Advanced Breast, Colon, Pancreatic, or Non-Small Cell Lung Cancer. U.S. National Institutes of Health.
Ref 525164ClinicalTrials.gov (NCT02423200) Clinical Pharmacology of p38 MAP Kinase Inhibitor, VX-745, in Mild Cognitive Impairment Due to Alzheimer's Disease (AD) or Mild AD. U.S. National Institutes of Health.
Ref 536836Agents in development for the treatment of diabetic nephropathy. Expert Opin Emerg Drugs. 2008 Sep;13(3):447-63.
Ref 541011(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. (Ligand id: 5668).
Ref 541019(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. (Ligand id: 5676).
Ref 541057(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. (Ligand id: 5719).
Ref 544340Myelodysplastic Syndromes: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2011 January; 9(1): 30-56.
Ref 547541Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017152)
Ref 547810Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019505)
Ref 548224Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800023346)
Ref 525872Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors.
Ref 526355J Med Chem. 2002 Jun 20;45(13):2733-40.From imidazoles to pyrimidines: new inhibitors of cytokine release.
Ref 526530Bioorg Med Chem Lett. 2003 Feb 10;13(3):347-50.Imidazopyrimidines, potent inhibitors of p38 MAP kinase.
Ref 526668J Med Chem. 2003 Jul 17;46(15):3230-44.Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes.
Ref 526904J Med Chem. 2003 Dec 18;46(26):5651-62.Synthesis and structure-activity relationship of aminobenzophenones. A novel class of p38 MAP kinase inhibitors with high antiinflammatory activity.
Ref 527308J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole.
Ref 536458Rapid synthesis of VX-745: p38 MAP kinase inhibition in Werner syndrome cells. Bioorg Med Chem Lett. 2007 Sep 15;17(18):5107-10. Epub 2007 Jul 13.
Ref 536836Agents in development for the treatment of diabetic nephropathy. Expert Opin Emerg Drugs. 2008 Sep;13(3):447-63.
Ref 536961P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis. J Inflamm (Lond). 2008 Dec 4;5:22.
Ref 536977Phosphorylation of Ewing's sarcoma protein (EWS) and EWS-Fli1 in response to DNA damage. Biochem J. 2009 Mar 15;418(3):625-34.
Ref 537039Inhibition of p38: has the fat lady sung? Arthritis Rheum. 2009 Feb;60(2):317-20.
Ref 549786KC706, an Oral p38 MAP Kinase Inhibitor, Increases HDL-C. Circulation. 2007;116:II_126.
Ref 550225Array BioPharma's ARRY-797 Meets Primary Endpoint in Clinical Proof of Concept Trial in Osteoarthritis Patients Whose Pain is Poorly Controlled by NSAIDs
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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