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 journalArticlepeer-review

    39 Citations (Scopus)


    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 of 0.162 ± 0.006 µM and in cells with a cellular EC 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 (S) 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
    Publication statusPublished - Dec 2013


    • Azepines
    • Cells, Cultured
    • Dose-Response Relationship, Drug
    • Enzyme Activation
    • HEK293 Cells
    • HeLa Cells
    • Humans
    • Mitogen-Activated Protein Kinase 7
    • Models, Molecular
    • Molecular Structure
    • Protein Kinase Inhibitors
    • Protein-Serine-Threonine Kinases
    • Pyrimidines
    • Structure-Activity Relationship


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