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

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42 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 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
Publication statusPublished - 2013

Bibliographical note

Funding Information:
We wish to thank Life Technologies Corporation, SelectScreen Kinase Profiling Service for performing enzymatic biochemical kinase profiling, DiscovRx for performing KINOMEscan profiling. This work was supported by NIH grant P41 GM079575 -03 (N. Gray) and the Medical Research Council (D. Alessi), the Michael J Fox foundation for Parkinson's disease research (N. Gray & D. Alessi), the pharmaceutical companies supporting the DSTT ( AstraZeneca, Boehringer-Ingelheim , GlaxoSmithKline , Merck KgaA and Pfizer ) (D. Alessi), the NIH grant CA079871 and CA114059 (J.-D. Lee) and funds from the Tobacco-Related Disease, Research Program of the University of California , 19XT-0084, (J.-D. Lee), and by the Spanish Ministerio de Educación grant BFU2007-60268 (J.M. Lizcano). JME, and SK are grateful for financial support by the SGC, a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research , the Canada Foundation for Innovation , Genome Canada , GlaxoSmithKline, Pfizer, Eli Lilly , Takeda , AbbVie , the Novartis Research Foundation , the Ontario Ministry of Research and Innovation and the Wellcome Trust .


  • 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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