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

doi:10.1021/ml100304b

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

KU-KIST Graduate School of Converging Science and Technology

Research output: Contribution to journal › Article › peer-review

54 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 (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 (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 language	English
Pages (from-to)	195-200
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	2
Issue number	3
DOIs	https://doi.org/10.1021/ml100304b
Publication status	Published - 2011 Mar 10

Keywords

BMK1
ERK5
MAPK

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml100304b

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title = "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 (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.",

keywords = "BMK1, ERK5, MAPK",

author = "Xianming Deng and Qingkai Yang and Nicholas Kwiatkowski and Taebo Sim and Ultan McDermott and Settleman, {Jeffrey E.} and Lee, {Jiing Dwan} and Gray, {Nathanael S.}",

year = "2011",

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doi = "10.1021/ml100304b",

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volume = "2",

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journal = "ACS Medicinal Chemistry Letters",

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AU - Deng, Xianming

AU - Yang, Qingkai

AU - Kwiatkowski, Nicholas

AU - Sim, Taebo

AU - McDermott, Ultan

AU - Settleman, Jeffrey E.

AU - Lee, Jiing Dwan

AU - Gray, Nathanael S.

PY - 2011/3/10

Y1 - 2011/3/10

N2 - 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.

AB - 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.

KW - BMK1

KW - ERK5

KW - MAPK

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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

Keywords

ASJC Scopus subject areas

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