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Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors
- Source :
- Bioorganicmedicinal chemistry letters. 30(22)
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Models, Molecular
Protein crystal structure
Clinical Biochemistry
Pharmaceutical Science
Crystallography, X-Ray
01 natural sciences
Biochemistry
Structure-Activity Relationship
Drug Discovery
Humans
Molecular Biology
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase 6
biology
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Chemistry
Kinase
Organic Chemistry
Assay
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Mitogen-activated protein kinase
biology.protein
Molecular Medicine
Selectivity
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 30
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....3858da554ad1df173dccde2103b256c7