Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control

Alex M. Aronov; Tang Qing; Gabriel Martinez-Botella; Guy W. Bemis; Jingrong Cao; Guanjing Chen; Nigel P. Ewing; Pamella J. Ford; Ursula A. Germann; Jeremy Green; Michael R. Hale; Marc Jacobs; James W. Janetka; Francois Maltais; William Markland; Mark N. Namchuk; Suganthini Nanthakumar; Srinivasu Poondru; Judy Straub; Ernst Ter Haar; Xie Xiaoling

doi:10.1021/jm900630q

Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control

Alex M. Aronov, Tang Qing, Gabriel Martinez-Botella, Guy W. Bemis, Jingrong Cao, Guanjing Chen, Nigel P. Ewing, Pamella J. Ford, Ursula A. Germann, Jeremy Green, Michael R. Hale, Marc Jacobs, James W. Janetka, Francois Maltais, William Markland, Mark N. Namchuk, Suganthini Nanthakumar, Srinivasu Poondru, Judy Straub, Ernst Ter HaarXie Xiaoling

Research output: Contribution to journal › Article

104 Scopus citations

Abstract

The Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is a key target in anticancer drug design. A novel series of pyrimidylpyrrole ERK inhibitors has been identified. Discovery of a conformational change for lead compound 2, when bound to ERK2 relative to antitarget GSK3, enabled structure-guided selectivity optimization, which led to the discovery of 11e, a potent, selective, and orally bioavailable inhibitor of ERK.

Original language	English
Pages (from-to)	6362-6368
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	20
DOIs	https://doi.org/10.1021/jm900630q
State	Published - Oct 22 2009
Externally published	Yes

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Aronov, A. M., Qing, T., Martinez-Botella, G., Bemis, G. W., Cao, J., Chen, G., Ewing, N. P., Ford, P. J., Germann, U. A., Green, J., Hale, M. R., Jacobs, M., Janetka, J. W., Maltais, F., Markland, W., Namchuk, M. N., Nanthakumar, S., Poondru, S., Straub, J., ... Xiaoling, X. (2009). Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control. Journal of Medicinal Chemistry, 52(20), 6362-6368. https://doi.org/10.1021/jm900630q

Aronov, Alex M. ; Qing, Tang ; Martinez-Botella, Gabriel ; Bemis, Guy W. ; Cao, Jingrong ; Chen, Guanjing ; Ewing, Nigel P. ; Ford, Pamella J. ; Germann, Ursula A. ; Green, Jeremy ; Hale, Michael R. ; Jacobs, Marc ; Janetka, James W. ; Maltais, Francois ; Markland, William ; Namchuk, Mark N. ; Nanthakumar, Suganthini ; Poondru, Srinivasu ; Straub, Judy ; Ter Haar, Ernst ; Xiaoling, Xie. / Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 20. pp. 6362-6368.

@article{1627e097128e4875a096b7c97ff5684f,

title = "Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control",

abstract = "The Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is a key target in anticancer drug design. A novel series of pyrimidylpyrrole ERK inhibitors has been identified. Discovery of a conformational change for lead compound 2, when bound to ERK2 relative to antitarget GSK3, enabled structure-guided selectivity optimization, which led to the discovery of 11e, a potent, selective, and orally bioavailable inhibitor of ERK.",

author = "Aronov, {Alex M.} and Tang Qing and Gabriel Martinez-Botella and Bemis, {Guy W.} and Jingrong Cao and Guanjing Chen and Ewing, {Nigel P.} and Ford, {Pamella J.} and Germann, {Ursula A.} and Jeremy Green and Hale, {Michael R.} and Marc Jacobs and Janetka, {James W.} and Francois Maltais and William Markland and Namchuk, {Mark N.} and Suganthini Nanthakumar and Srinivasu Poondru and Judy Straub and {Ter Haar}, Ernst and Xie Xiaoling",

year = "2009",

month = oct,

day = "22",

doi = "10.1021/jm900630q",

language = "English",

volume = "52",

pages = "6362--6368",

journal = "Journal of Medicinal Chemistry",

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Aronov, AM, Qing, T, Martinez-Botella, G, Bemis, GW, Cao, J, Chen, G, Ewing, NP, Ford, PJ, Germann, UA, Green, J, Hale, MR, Jacobs, M, Janetka, JW, Maltais, F, Markland, W, Namchuk, MN, Nanthakumar, S, Poondru, S, Straub, J, Ter Haar, E & Xiaoling, X 2009, 'Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control', Journal of Medicinal Chemistry, vol. 52, no. 20, pp. 6362-6368. https://doi.org/10.1021/jm900630q

Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control. / Aronov, Alex M.; Qing, Tang; Martinez-Botella, Gabriel; Bemis, Guy W.; Cao, Jingrong; Chen, Guanjing; Ewing, Nigel P.; Ford, Pamella J.; Germann, Ursula A.; Green, Jeremy; Hale, Michael R.; Jacobs, Marc; Janetka, James W.; Maltais, Francois; Markland, William; Namchuk, Mark N.; Nanthakumar, Suganthini; Poondru, Srinivasu; Straub, Judy; Ter Haar, Ernst; Xiaoling, Xie.

In: Journal of Medicinal Chemistry, Vol. 52, No. 20, 22.10.2009, p. 6362-6368.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control

AU - Aronov, Alex M.

AU - Qing, Tang

AU - Martinez-Botella, Gabriel

AU - Bemis, Guy W.

AU - Cao, Jingrong

AU - Chen, Guanjing

AU - Ewing, Nigel P.

AU - Ford, Pamella J.

AU - Germann, Ursula A.

AU - Green, Jeremy

AU - Hale, Michael R.

AU - Jacobs, Marc

AU - Janetka, James W.

AU - Maltais, Francois

AU - Markland, William

AU - Namchuk, Mark N.

AU - Nanthakumar, Suganthini

AU - Poondru, Srinivasu

AU - Straub, Judy

AU - Ter Haar, Ernst

AU - Xiaoling, Xie

PY - 2009/10/22

Y1 - 2009/10/22

N2 - The Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is a key target in anticancer drug design. A novel series of pyrimidylpyrrole ERK inhibitors has been identified. Discovery of a conformational change for lead compound 2, when bound to ERK2 relative to antitarget GSK3, enabled structure-guided selectivity optimization, which led to the discovery of 11e, a potent, selective, and orally bioavailable inhibitor of ERK.

AB - The Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is a key target in anticancer drug design. A novel series of pyrimidylpyrrole ERK inhibitors has been identified. Discovery of a conformational change for lead compound 2, when bound to ERK2 relative to antitarget GSK3, enabled structure-guided selectivity optimization, which led to the discovery of 11e, a potent, selective, and orally bioavailable inhibitor of ERK.

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