6YLC

Biochemical, Cellular and Structural Characterization of Novel ERK3 Inhibitors

Summary for 6YLC

• Entry DOI: 10.2210/pdb6ylc/pdb
• Related: 6YKY
• Descriptor: Mitogen-activated protein kinase 6, 5-fluoranyl-2-[5-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]benzenecarbonitrile (3 entities in total)
• Functional Keywords: human mitogen activated protein kinase 6 (mapk6), erk3, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 146448.41

Authors

Graedler, U. (deposition date: 2020-04-07, release date: 2020-09-23, Last modification date: 2024-01-24)

Primary citation

Gradler, U.,Busch, M.,Leuthner, B.,Raba, M.,Burgdorf, L.,Lehmann, M.,Linde, N.,Esdar, C.
Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors.
Bioorg.Med.Chem.Lett., 30:127551-127551, 2020

PubMed 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 ICs. This novel series provides valuable tool compounds to further investigate the biological function and activation mechanism of ERK3.

PubMed: 32927028
DOI: 10.1016/j.bmcl.2020.127551

Experimental method

X-RAY DIFFRACTION (2.43 Å)