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

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

  • J Med Chem. 2009 Oct 22;52(20):6362-8. doi: 10.1021/jm900630q.
Alex M Aronov 1,  Qing Tang,  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,  Xiaoling Xie
Affiliations

Affiliation

  • 1 Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139-4242, USA. [email protected]
PMID: 19827834 DOI: 10.1021/jm900630q
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.

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