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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.

Original publication




Journal article


Eur J Med Chem

Publication Date





758 - 767


2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-biphenyl, BMK1, Benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-one, DCAMKL2, DIEA, DMA, EGF, ERK5, ERK5 inhibitor, HCC, Kinase selectivity, LRRK2, MAP kinase kinase 5, MAPK, MEK5, N,N-diisopropylethylamine, N,N-dimethylacetamide, PLK, PML, Pd(2)(dba)(3), RSK, SAR, X-phos, XVBGRTMNFNMINE-UHFFFAOYSA-N, big MAP kinase 1, doublecortin and CaM kinase-like 2, epidermal growth factor, extracelluar-signal-regulated kinase 5, hepatocellular carcinoma, leucine rich repeat kinase 2, mitogen-activated protein kinase, mitogen-activated protein kinase 7, polo-like kinase, promyelocytic leukemia protein, ribosomal S6 kinase, structure–activity relationship, tris(dibenzylideneacetone)dipalladium-(0), Azepines, Cells, Cultured, Dose-Response Relationship, Drug, Enzyme Activation, HEK293 Cells, HeLa Cells, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Mitogen-Activated Protein Kinase 7, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Pyrimidines, Structure-Activity Relationship