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

Xianming Deng; Jonathan M. Elkins; Jinwei Zhang; Qingkai Yang; Tatiana Erazo; Nestor Gomez; Hwan Geun Choi; Jinhua Wang; Nicolas Dzamko; Jiing-Dwan Lee; Taebo Sim; NamDoo Kim; Dario R. Alessi; Jose M. Lizcano; Stefan Knapp; Nathanael S. Gray

doi:10.1016/j.ejmech.2013.10.052

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

Xianming Deng, Jonathan M. Elkins, Jinwei Zhang, Qingkai Yang, Tatiana Erazo, Nestor Gomez, Hwan Geun Choi, Jinhua Wang, Nicolas Dzamko, Jiing-Dwan Lee, Taebo Sim, NamDoo Kim, Dario R. Alessi, Jose M. Lizcano, Stefan Knapp, Nathanael S. Gray

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

39 Citations (Scopus)

Abstract

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 IC of 0.162 ± 0.006 µM and in cells with a cellular EC 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 (S) 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 language	English
Pages (from-to)	758-767
Number of pages	10
Journal	European Journal of Medicinal Chemistry
Volume	70
DOIs	https://doi.org/10.1016/j.ejmech.2013.10.052
Publication status	Published - Dec 2013

Keywords

Azepines
Cells, Cultured
Dose-Response Relationship, Drug
Enzyme Activation
HEK293 Cells
HeLa Cells
Humans
Mitogen-Activated Protein Kinase 7
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors
Protein-Serine-Threonine Kinases
Pyrimidines
Structure-Activity Relationship

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10.1016/j.ejmech.2013.10.052

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Deng, X., Elkins, J. M., Zhang, J., Yang, Q., Erazo, T., Gomez, N., Choi, H. G., Wang, J., Dzamko, N., Lee, J-D., Sim, T., Kim, N., Alessi, D. R., Lizcano, J. M., Knapp, S., & Gray, N. S. (2013). Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones. European Journal of Medicinal Chemistry, 70, 758-767. https://doi.org/10.1016/j.ejmech.2013.10.052

@article{91d20ac1ed574e80b62036751d4507ce,

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

abstract = "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 IC of 0.162 ± 0.006 µM and in cells with a cellular EC 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 (S) 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.",

keywords = "Azepines, Cells, Cultured, Dose-Response Relationship, Drug, Enzyme Activation, HEK293 Cells, HeLa Cells, Humans, Mitogen-Activated Protein Kinase 7, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Pyrimidines, Structure-Activity Relationship",

author = "Xianming Deng and Elkins, {Jonathan M.} and Jinwei Zhang and Qingkai Yang and Tatiana Erazo and Nestor Gomez and Choi, {Hwan Geun} and Jinhua Wang and Nicolas Dzamko and Jiing-Dwan Lee and Taebo Sim and NamDoo Kim and Alessi, {Dario R.} and Lizcano, {Jose M.} and Stefan Knapp and Gray, {Nathanael S.}",

year = "2013",

month = dec,

doi = "10.1016/j.ejmech.2013.10.052",

language = "English",

volume = "70",

pages = "758--767",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier",

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Deng, X, Elkins, JM, Zhang, J, Yang, Q, Erazo, T, Gomez, N, Choi, HG, Wang, J, Dzamko, N, Lee, J-D, Sim, T, Kim, N, Alessi, DR, Lizcano, JM, Knapp, S & Gray, NS 2013, 'Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones', European Journal of Medicinal Chemistry, vol. 70, pp. 758-767. https://doi.org/10.1016/j.ejmech.2013.10.052

TY - JOUR

T1 - Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones

AU - Deng, Xianming

AU - Elkins, Jonathan M.

AU - Zhang, Jinwei

AU - Yang, Qingkai

AU - Erazo, Tatiana

AU - Gomez, Nestor

AU - Choi, Hwan Geun

AU - Wang, Jinhua

AU - Dzamko, Nicolas

AU - Lee, Jiing-Dwan

AU - Sim, Taebo

AU - Kim, NamDoo

AU - Alessi, Dario R.

AU - Lizcano, Jose M.

AU - Knapp, Stefan

AU - Gray, Nathanael S.

PY - 2013/12

Y1 - 2013/12

N2 - 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 IC of 0.162 ± 0.006 µM and in cells with a cellular EC 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 (S) 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.

AB - 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 IC of 0.162 ± 0.006 µM and in cells with a cellular EC 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 (S) 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.

KW - Azepines

KW - Cells, Cultured

KW - Dose-Response Relationship, Drug

KW - Enzyme Activation

KW - HEK293 Cells

KW - HeLa Cells

KW - Humans

KW - Mitogen-Activated Protein Kinase 7

KW - Models, Molecular

KW - Molecular Structure

KW - Protein Kinase Inhibitors

KW - Protein-Serine-Threonine Kinases

KW - Pyrimidines

KW - Structure-Activity Relationship

UR - http://www.scopus.com/inward/record.url?scp=84887384933&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2013.10.052

DO - 10.1016/j.ejmech.2013.10.052

M3 - Article

C2 - 24239623

AN - SCOPUS:84887384933

SN - 0223-5234

VL - 70

SP - 758

EP - 767

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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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Keywords

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A Systematic Investigation into the Pathogenesis and Course of Parkinson's Syndrome (Wellcome Trust and MRC Neurodegenerative Diseases Initiative) (Joint with University College London)

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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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Keywords

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A Systematic Investigation into the Pathogenesis and Course of Parkinson's Syndrome (Wellcome Trust and MRC Neurodegenerative Diseases Initiative) (Joint with University College London)

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