title: Synthesis and in vivo activity of MK2 and MK2 substrate-selective p38alpha(MAPK) inhibitors in Werner syndrome cells.
abstract: A benzopyranopyridine inhibitor of mitogen-activated protein kinase-activated protein kinase 2 (MK2) is prepared rapidly and efficiently in one step using microwave dielectric heating, whereas a substrate-selective p38 MAPK inhibitor was prepared using conventional heating techniques. The former had MK2 inhibitory activity above 2.5 microM concentration, whereas the latter showed no MK2 inhibition at 10 microM. However, rather than rescuing the reduced cellular growth rate and aged morphology of hTERT-immortalised WS dermal fibroblasts, both induce a state resembling stress-induced cellular senescence, suggesting that these inhibitors may have limited therapeutic use.
authors.affiliation: Department of Pathology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Terence
authors.initials: T
authors.lastname: Davis
authors.forename: Mark C
authors.initials: MC
authors.lastname: Bagley
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Dix
authors.forename: Paola G S
authors.initials: PG
authors.lastname: Murziani
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Rokicki
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Widdowson
authors.forename: Jameel M
authors.initials: JM
authors.lastname: Zayed
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Bachler
authors.forename: David
authors.initials: D
authors.lastname: Kipling
mesh_terms: D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013379:Substrate Specificity; D014898:Werner Syndrome / Q000201:enzymology*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D048308:Mitogen-Activated Protein Kinase 14; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2