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Article

Flipped Out: Structure-Guided Design of Selective Pyrazolylpyrrole ERK Inhibitors^‡

Supporting Info

Alex M. Aronov,* Christopher Baker, Guy W. Bemis, Jingrong Cao, Guanjing Chen, Pamella J. Ford, Ursula A. Germann, Jeremy Green, Michael R. Hale, Marc Jacobs, James W. Janetka, Francois Maltais, Gabriel Martinez-Botella, Mark N. Namchuk, Judy Straub, Qing Tang, and Xiaoling Xie

Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139-4242

J. Med. Chem., 2007, 50 (6), pp 1280–1287

DOI: 10.1021/jm061381f

Publication Date (Web): February 15, 2007

‡

The atomic coordinates for ERK2 and JNK3 complexes have been deposited in the Protein Data Bank under accession numbers 2OJG, 2OJI, 2OJJ, and 2OK1.

To whom correspondence should be addressed. Telephone: (617) 444-6100. Fax: (617) 444-6566. E-mail: alex_aronov@vrtx.com.

Abstract

The Ras/Raf/MEK/ERK signal transduction is a key oncogenic pathway implicated in a variety of human cancers. We have identified a novel series of pyrazolylpyrroles as inhibitors of ERK. Aided by the discovery of two distinct binding modes for the pyrazolylpyrrole scaffold, structure-guided optimization culminated in the discovery of 6p, a potent and selective inhibitor of ERK.

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Published In Issue March 22, 2007
Received November 30, 2006

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Article

Flipped Out: Structure-Guided Design of Selective Pyrazolylpyrrole ERK Inhibitors^‡