Discovery of a benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a potent and selective inhibitor of big MAP kinase 1

Xianming Deng, Qingkai Yang, Nicholas Kwiatkowski, Taebo Sim, Ultan McDermott, Jeffrey E. Settleman, Jiing Dwan Lee, Nathanael S. Gray

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Kinome-wide selectivity profiling of a collection of 2-amino-pyrido[2,3-d] pyrimidines followed by cellular structure-activity relationship-guided optimization resulted in the identification of moderately potent and selective inhibitors of BMK1/ERK5 exemplified by 11, 18, and 21. For example, 11 possesses a dissociation constant (Kd) for BMK1 of 19 nM, a cellular IC 50 for inhibiting epidermal growth factor induced BMK1 autophosphorylation of 0.19 ± 0.04 μM, and an Ambit KINOMEscan selectivity score (S5) of 0.035. Inhibitors 18 and 21 are also potent BMK1 inhibitors and possess favorable pharmacokinetic properties which enable their use as pharmacological probes of BMK1-dependent phenomena as well as starting points for further optimization efforts.

Original languageEnglish
Pages (from-to)195-200
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume2
Issue number3
DOIs
Publication statusPublished - 2011 Mar 10

Keywords

  • BMK1
  • ERK5
  • MAPK

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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    Deng, X., Yang, Q., Kwiatkowski, N., Sim, T., McDermott, U., Settleman, J. E., Lee, J. D., & Gray, N. S. (2011). Discovery of a benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a potent and selective inhibitor of big MAP kinase 1. ACS Medicinal Chemistry Letters, 2(3), 195-200. https://doi.org/10.1021/ml100304b