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:https://doi.org/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

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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 50 of 0.162 ± 0.006 μM and in cells with a cellular EC 50 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. © 2013 Elsevier Masson SAS. All rights reserved.

Original language	English
Pages (from-to)	758-767
Journal	European Journal of Medicinal Chemistry
Volume	70
DOIs	https://doi.org/10.1016/j.ejmech.2013.10.052
Publication status	Published - 1 Jan 2013

Keywords

Benzo[e]pyrimido-[5,4-b]diazepine-6(11H)- one
ERK5 inhibitor
Kinase selectivity

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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{8e621e8803f84b2db835801b87aae13c,

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 50 of 0.162 ± 0.006 μM and in cells with a cellular EC 50 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. {\textcopyright} 2013 Elsevier Masson SAS. All rights reserved.",

keywords = "Benzo[e]pyrimido-[5,4-b]diazepine-6(11H)- one, ERK5 inhibitor, Kinase selectivity",

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 Lee, {Jiing Dwan} and Taebo Sim and Namdoo Kim and Alessi, {Dario R.} and Lizcano, {Jose M.} and Stefan Knapp and Gray, {Nathanael S.}",

year = "2013",

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Deng, X, Elkins, JM, Zhang, J, Yang, Q, Erazo, T, Gomez, N, Choi, HG, Wang, J, Dzamko, N, Lee, JD, 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 - 2013/1/1

Y1 - 2013/1/1

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 50 of 0.162 ± 0.006 μM and in cells with a cellular EC 50 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. © 2013 Elsevier Masson SAS. All rights reserved.

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 50 of 0.162 ± 0.006 μM and in cells with a cellular EC 50 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. © 2013 Elsevier Masson SAS. All rights reserved.

KW - Benzo[e]pyrimido-[5,4-b]diazepine-6(11H)- one

KW - ERK5 inhibitor

KW - Kinase selectivity

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DO - https://doi.org/10.1016/j.ejmech.2013.10.052

M3 - Article

VL - 70

SP - 758

EP - 767

ER -

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

Abstract

Keywords

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