meridianin-g and 6-azaindole

A structure-activity relationship has been developed around the meridianin scaffold for inhibition of Dyrk1a. The compounds have been focussed on the inhibition of kinase Dyrk1a, as a means to retain the transcription factor NFAT in the nucleus. NFAT is responsible for up-regulation of genes responsible for the induction of a slow, oxidative skeletal muscle phenotype, which may be an effective treatment for diseases where exercise capacity is compromised. The SAR showed that while strong Dyrk1a binding was possible with the meridianin scaffold the compounds have no effect on NFAT localisation, however, by moving from the indole to a 6-azaindole scaffold both potent Dyrk1a binding and increased NFAT residence time in the nucleus were obtained - properties not observed with the reported Dyrk1a inhibitors. One compound was shown to be effective in an ex vivo muscle fiber assay. The increased biological activity is thought to arise from the added interaction between the azaindole nitrogen and the lysine residue in the back pocket.

Topics: Animals; Aza Compounds; Binding Sites; Cell Nucleus; Dyrk Kinases; Humans; Indole Alkaloids; Indoles; Inhibitory Concentration 50; Mice; Microscopy, Confocal; Molecular Docking Simulation; Muscle Fibers, Skeletal; NFATC Transcription Factors; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein-Tyrosine Kinases; Structure-Activity Relationship; Up-Regulation