Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones Academic Article uri icon

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  • 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.


  • Steinberg, Gregory
  • Deng, Xianming
  • Elkins, Jonathan M
  • Zhang, Jinwei
  • Yang, Qingkai
  • Erazo, Tatiana
  • Gomez, Nestor
  • Choi, Hwan Geun
  • Wang, Jinhua
  • Dzamko, Nicolas
  • Lee, Jiing-Dwan
  • Sim, Taebo
  • Kim, NamDoo
  • Alessi, Dario R
  • Lizcano, Jose M
  • Knapp, Stefan
  • Gray, Nathanael S

publication date

  • December 2013

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