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, Taebo Sim, Namdoo Kim, Dario R. Alessi, Jose M. Lizcano, Stefan Knapp, Nathanael S. Gray

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 IC 50 of 0.162 ± 0.006 μM and in cells with a cellular EC 50 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.

Original languageEnglish
Pages (from-to)758-767
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume70
DOIs
Publication statusPublished - 2013

Keywords

  • Benzo[e]pyrimido-[5,4-b]diazepine-6(11H)- one
  • ERK5 inhibitor
  • Kinase selectivity

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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    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. (2013). Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones. European Journal of Medicinal Chemistry, 70, 758-767. https://doi.org/10.1016/j.ejmech.2013.10.052