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Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors.

Aronov AM, Baker C, Bemis GW, Cao J, Chen G, Ford PJ, Germann UA, Green J, Hale MR, Jacobs M, Janetka JW, Maltais F, Martinez-Botella G, Namchuk MN, Straub J, Tang Q, Xie X

Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139-4242, USA. alex_aronov@vrtx.com

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.

Published 15 March 2007 in J Med Chem, 50(6): 1280-7.
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