Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTMUG9D)

• DTT Name: MAPK-activated protein kinase 2 (MAPKAPK2)
• Synonyms: MK2; MK-2; MAPKactivated protein kinase 2; MAPKAPK-2; MAPKAP-K2; MAPKAP kinase 2; MAP kinaseactivated protein kinase 2; MAP kinase-activated protein kinase 2
• Gene Name: MAPKAPK2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: MAPK2_HUMAN
• TTD ID: T21307
• EC Number: EC 2.7.11.1
• Sequence:
  MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIKKNAII
  DDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCPHIVRI
  VDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQYLHSI
  NIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVLGPEKY
  DKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVSEEVKM
  LIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHTSRVLKEDKERWEDVKEEMTSAL
  ATMRVDYEQIKIKKIEDASNPLLLKRRKKARALEAAALAH
• Function: Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the interaction with HSP90 proteins and inhibiting HSF1 homotrimerization, DNA-binding and transactivation activities. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to the dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impairment of their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to the regulation of the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity, leading to inhibition of dependent degradation of ARE-containing transcripts. Phosphorylates CEP131 in response to cellular stress induced by ultraviolet irradiation which promotes binding of CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar satellites. Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Stress-activated serine/threonine-protein kinase involved in cytokine production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  VEGF signaling pathway (hsa04370)
  Neurotrophin signaling pathway (hsa04722)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  p38MAPK events (R-HSA-171007)
• BioCyc Pathway: MetaCyc:HS08751-MON

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Zunsemetinib	DMNFNK7	Cryopyrin-associated periodic syndrome	4A60.1	Phase 2	[2]
CBP-501	DMCWVPU	Mesothelioma	2C51.2	Phase 1/2	[1]
MMI-0100	DMIMVEX	Airway inflammation	CA05	Phase 1	[3]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CMPD1	DMKNUYF	Discovery agent	N.A.	Investigative	[4]
PF-3644022	DM6KVIA	Discovery agent	N.A.	Investigative	[5]
PMID17480064C16	DM4IABG	Discovery agent	N.A.	Investigative	[6]
PMID19364658C33	DMSE1C3	Discovery agent	N.A.	Investigative	[7]

References

• [1] National Cancer Institute Drug Dictionary (drug id 577812).
• [2] Clinical pipeline report, company report or official report of Aclaris Therapeutics
• [3] 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: 2094).
• [4] Synthesis and in vivo activity of MK2 and MK2 substrate-selective p38alpha(MAPK) inhibitors in Werner syndrome cells. Bioorg Med Chem Lett. 2007 Dec 15;17(24):6832-5.
• [5] A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor alpha production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation. J Pharmacol Exp Ther. 2010 Jun;333(3):797-807.
• [6] Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). J Med Chem. 2007 May 31;50(11):2647-54.
• [7] Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem. 2009 May 1;17(9):3342-51.