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 muM and in cells with a cellular EC50 for inhibiting epidermal growth factor induced ERK5 autophosphorylation of 0.09 +/- 0.03 muM. 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.
Author(s):
PubMed:
24239623
Deng, X., Elkins, J. M., Zhang, J., Yang, Q., Erazo, T., Gomez, N., Choi, H. G., Wang, J., Dzamko, N., Lee, J. D., Sim, T., Kim, N., Alessi, D. R., Lizcano, J. M., Knapp, S., Gray, N. S.