Synthesis and in vivo activity of MK2 and MK2 substrate-selective p38alpha(MAPK) inhibitors in Werner syndrome cells

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 24; pp. 6832 - 6835
• Main Authors: Davis, Terence, Bagley, Mark C, Dix, Matthew C, Murziani, Paola G S, Rokicki, Michal J, Widdowson, Caroline S, Zayed, Jameel M, Bachler, Marcus A, Kipling, David
• Format: Journal Article
• Language: English
• Published: England 15.12.2007
• Subjects: Cell Line; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 14 - metabolism; Molecular Structure; Phosphorylation - drug effects; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Substrate Specificity; Werner Syndrome - enzymology
• ISSN: 1464-3405

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.