Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control.
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.
Aronov
Alex M
AM
Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139-4242, USA. alex_aronov@vrtx.com
Tang
Qing
Q
Martinez-Botella
Gabriel
G
Bemis
Guy W
GW
Cao
Jingrong
J
Chen
Guanjing
G
Ewing
Nigel P
NP
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
Markland
William
W
Namchuk
Mark N
MN
Nanthakumar
Suganthini
S
Poondru
Srinivasu
S
Straub
Judy
J
ter Haar
Ernst
E
Xie
Xiaoling
X
D015195:Drug Design; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D013379:Substrate Specificity
D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D048049:Extracellular Signal-Regulated MAP Kinases