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Eur J Med Chem. 2013;70:758-67. doi: 10.1016/j.ejmech.2013.10.052. Epub 2013 Oct 29.

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

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Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Ave, SGM 628, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave, SGM 628, Boston, MA 02115, USA.


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.


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)

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