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

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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 languageEnglish
Pages (from-to)6362-6368
Number of pages7
JournalJournal of Medicinal Chemistry
Volume52
Issue number20
DOIs
StatePublished - Oct 22 2009
Externally publishedYes

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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