Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors.
Triazolo[4,5-d]pyrimidin-5-amines were identified from kinase selectivity screening as novel ERK3 inhibitors with sub-100 nanomolar potencies in a biochemical assay using MK5 as substrate and with an attractive kinase selectivity profile. ERK3 crystal structures clarified the inhibitor binding mode in the ATP pocket with impact on A-loop, GC-loop and αC-helix conformations suggesting a potential structural link towards MK5 interaction via the FHIEDE motif. The inhibitors also showed sub-100 nM potencies in a cellular ERK3 NanoBRET assay and with excellent correlation to the biochemical IC50s. This novel series provides valuable tool compounds to further investigate the biological function and activation mechanism of ERK3.
['Grädler|Ulrich|U|', 'Busch|Michael|M|', 'Leuthner|Birgitta|B|', 'Raba|Michael|M|', 'Burgdorf|Lars|L|', 'Lehmann|Martin|M|', 'Linde|Nina|N|', 'Esdar|Christina|C|']
D018360:Crystallography, X-Ray D004305:Dose-Response Relationship, Drug D006801:Humans D048053:Mitogen-Activated Protein Kinase 6 D008958:Models, Molecular D015394:Molecular Structure D047428:Protein Kinase Inhibitors D013329:Structure-Activity Relationship
ERK3 Cellular NanoBRET assay Kinase inhibitor Mitogen activated protein kinase Protein crystal structure