Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones
- Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones
- Xianming Deng; Jonathan M. Elkins; Jinwei Zhang; Qingkai Yang; Tatiana Erazo; Nestor Gomez; Hwan Geun Choi; Jinhua Wang; Nicolas Dzamko; Jiing-Dwan Lee; 심태보; NamDoo Kim; Dario R. Alessi; Jose M. Lizcano; Stefan Knapp; Nathanael S. Gray
- ERK5 inhibitor; Kinase selectivity; Benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one
- Issue Date
- European journal of medicinal chemistry
- VOL 70, 758-767
- The benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one core was discovered as a novel ERK5 (also known as MAPK7 and BMK1) inhibitor scaffold, previously. Further structure–activity relationship studies of this scaffold led to the discovery of ERK5-IN-1 (26) as the most selective and potent ERK5 inhibitor reported to date. 26 potently inhibits ERK5 biochemically with an IC50 of 0.162 ± 0.006 μM and in cells with a cellular EC50 for inhibiting epidermal growth factor induced ERK5 autophosphorylation of 0.09 ± 0.03 μM. Furthermore, 26 displays excellent selectivity over other kinases with a KINOMEscan selectivity score (S10) of 0.007, and exhibits exceptional bioavailability (F%) of 90% in mice. 26 will serve as a valuable tool compound to investigate the ERK5 signaling pathway and as a starting point for developing an ERK5 directed therapeutic agent.
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