Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127551. doi: 10.1016/j.bmcl.2020.127551. Epub 2020 Sep 11.


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.

Keywords: Cellular NanoBRET assay; ERK3; Kinase inhibitor; Mitogen activated protein kinase; Protein crystal structure.

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Mitogen-Activated Protein Kinase 6 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 6 / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship


  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase 6