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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.

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 (K(d)) 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 (S(5)) 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.

SUBMITTER: Deng X

PROVIDER: S-EPMC3055678 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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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.

Deng Xianming X Yang Qingkai Q Kwiatkowski Nicholas N Sim Taebo T McDermott Ultan U Settleman Jeffrey E JE Lee Jiing-Dwan JD Gray Nathanael S NS

ACS medicinal chemistry letters 20110112 3

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 (K(d)) 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 ...[more]

PMID: 21412406

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