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

Aronov A.M., Tang Q., 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., ter Haar E., Xie X.

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.

J. Med. Chem. 52:6362-6368(2009) [PubMed] [Europe PMC]

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