title: Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors.
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.
authors.affiliation: Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139-4242, USA. alex_aronov@vrtx.com
authors.forename: Alex M
authors.initials: AM
authors.lastname: Aronov
authors.forename: Christopher
authors.initials: C
authors.lastname: Baker
authors.forename: Guy W
authors.initials: GW
authors.lastname: Bemis
authors.forename: Jingrong
authors.initials: J
authors.lastname: Cao
authors.forename: Guanjing
authors.initials: G
authors.lastname: Chen
authors.forename: Pamella J
authors.initials: PJ
authors.lastname: Ford
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Germann
authors.forename: Jeremy
authors.initials: J
authors.lastname: Green
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hale
authors.forename: Marc
authors.initials: M
authors.lastname: Jacobs
authors.forename: James W
authors.initials: JW
authors.lastname: Janetka
authors.forename: Francois
authors.initials: F
authors.lastname: Maltais
authors.forename: Gabriel
authors.initials: G
authors.lastname: Martinez-Botella
authors.forename: Mark N
authors.initials: MN
authors.lastname: Namchuk
authors.forename: Judy
authors.initials: J
authors.lastname: Straub
authors.forename: Qing
authors.initials: Q
authors.lastname: Tang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xie
mesh_terms: 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
chemical_list: 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