title: Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control.
abstract: 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.
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: Qing
authors.initials: Q
authors.lastname: Tang
authors.forename: Gabriel
authors.initials: G
authors.lastname: Martinez-Botella
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: Nigel P
authors.initials: NP
authors.lastname: Ewing
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: William
authors.initials: W
authors.lastname: Markland
authors.forename: Mark N
authors.initials: MN
authors.lastname: Namchuk
authors.forename: Suganthini
authors.initials: S
authors.lastname: Nanthakumar
authors.forename: Srinivasu
authors.initials: S
authors.lastname: Poondru
authors.forename: Judy
authors.initials: J
authors.lastname: Straub
authors.forename: Ernst
authors.initials: E
authors.lastname: ter Haar
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xie
mesh_terms: 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
chemical_list: D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D048049:Extracellular Signal-Regulated MAP Kinases