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
  • 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.