Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT73U6C)

• DTT Name: Stress-activated protein kinase 2b (p38 beta)
• Synonyms: Stress-activated protein kinase-2; SAPK2b; SAPK2; PRKM11; P38b; P38-2; P38 Mitogen-activated protein kinase beta; Mitogen-activated protein kinase p38 beta; Mitogen-activated protein kinase 11; MAPK 11; MAP kinase p38 beta; MAP kinase 11
• Gene Name: MAPK11
• DTT Type: Clinical trial target; [1]
• Related Disease:
  Alzheimer disease [ICD-11: 8A20]
  Rheumatoid arthritis [ICD-11: FA20]
• BioChemical Class: Kinase
• UniProt ID: MK11_HUMAN
• TTD ID: T55729
• EC Number: EC 2.7.11.24
• Sequence:
  MSGPRAGFYRQELNKTVWEVPQRLQGLRPVGSGAYGSVCSAYDARLRQKVAVKKLSRPFQ
  SLIHARRTYRELRLLKHLKHENVIGLLDVFTPATSIEDFSEVYLVTTLMGADLNNIVKCQ
  ALSDEHVQFLVYQLLRGLKYIHSAGIIHRDLKPSNVAVNEDCELRILDFGLARQADEEMT
  GYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLQGKALFPGSDYIDQLKRIMEVVG
  TPSPEVLAKISSEHARTYIQSLPPMPQKDLSSIFRGANPLAIDLLGRMLVLDSDQRVSAA
  EALAHAYFSQYHDPEDEPEAEPYDESVEAKERTLEEWKELTYQEVLSFKPPEPPKPPGSL
  EIEQ
• Function: MAPK11 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. MAPK11 functions are mostly redundant with those of MAPK14. 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. 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. 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. Additional examples of p38 MAPK substrates are the 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. 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)
  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)

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
VX-745	DMJAEG6	Alzheimer disease	8A20	Phase 2	[1]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SB 235699	DMNH8XU	Psoriasis vulgaris	EA90	Discontinued in Phase 1	[1], [2]

13 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[3]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[4]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[4]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[4]
KT-5720	DM9J50F	Discovery agent	N.A.	Investigative	[4]
L-779450	DM51B74	Discovery agent	N.A.	Investigative	[5]
ML-3163	DM3S5UC	Discovery agent	N.A.	Investigative	[6]
ML-3375	DMXJY6W	Discovery agent	N.A.	Investigative	[7]
ML-3403	DMTQWI8	Discovery agent	N.A.	Investigative	[7]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[4]
Ro31-8220	DMDJLF0	Discovery agent	N.A.	Investigative	[4]
RWJ-68354	DMNLVRS	Discovery agent	N.A.	Investigative	[8]
STAUROSPORINONE	DMU2H4K	Discovery agent	N.A.	Investigative	[4]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Psoriasis	EA90	Skin	3.40E-03	-0.12	-0.29

References

• [1] Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci. 2002 Jan;23(1):40-5.
• [2] Synthesis and structure-activity relationship of aminobenzophenones. A novel class of p38 MAP kinase inhibitors with high antiinflammatory activity. J Med Chem. 2003 Dec 18;46(26):5651-62.
• [3] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.
• [4] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [5] The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett. 2006 Jan 15;16(2):378-81.
• [6] From imidazoles to pyrimidines: new inhibitors of cytokine release. J Med Chem. 2002 Jun 20;45(13):2733-40.
• [7] Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes. J Med Chem. 2003 Jul 17;46(15):3230-44.
• [8] Imidazopyrimidines, potent inhibitors of p38 MAP kinase. Bioorg Med Chem Lett. 2003 Feb 10;13(3):347-50.