Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors.
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.
Aronov
Alex M
AM
Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139-4242, USA. alex_aronov@vrtx.com
Baker
Christopher
C
Bemis
Guy W
GW
Cao
Jingrong
J
Chen
Guanjing
G
Ford
Pamella J
PJ
Germann
Ursula A
UA
Green
Jeremy
J
Hale
Michael R
MR
Jacobs
Marc
M
Janetka
James W
JW
Maltais
Francois
F
Martinez-Botella
Gabriel
G
Namchuk
Mark N
MN
Straub
Judy
J
Tang
Qing
Q
Xie
Xiaoling
X
D001665:Binding Sites; D018360:Crystallography, X-Ray; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism
C519101:N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-4-(4-(3-chlorophenyl)-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxamide; D011720:Pyrazoles; D011758:Pyrroles; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3