title: Discovery of novel allosteric mitogen-activated protein kinase kinase (MEK) 1,2 inhibitors possessing bidentate Ser212 interactions.
abstract: Using structure-based design, two novel series of highly potent biaryl amine mitogen-activated protein kinase kinase (MEK) inhibitors have been discovered. These series contain an H-bond acceptor, in a shifted position compared with previously disclosed compounds, and an adjacent H-bond donor, resulting in a bidentate interaction with the Ser212 residue of MEK1. The most potent compound identified, 1 (G-894), is orally active in in vivo pharmacodynamic and tumor xenograft models.
authors.affiliation: Argenta, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK. robert.heald@glpg.com
authors.forename: Robert A
authors.initials: RA
authors.lastname: Heald
authors.forename: Philip
authors.initials: P
authors.lastname: Jackson
authors.forename: Pascal
authors.initials: P
authors.lastname: Savy
authors.forename: Mark
authors.initials: M
authors.lastname: Jones
authors.forename: Emanuela
authors.initials: E
authors.lastname: Gancia
authors.forename: Brenda
authors.initials: B
authors.lastname: Burton
authors.forename: Richard
authors.initials: R
authors.lastname: Newman
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Chan
authors.forename: Edna
authors.initials: E
authors.lastname: Choo
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Patrick
authors.initials: P
authors.lastname: Rudewicz
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Steve
authors.initials: S
authors.lastname: Price
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006860:Hydrogen Bonding; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D051381:Rats; D012694:Serine / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C574759:4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (2-hydroxyethoxy)amide; D000970:Antineoplastic Agents; D001572:Benzofurans; D052160:Benzothiazoles; D007191:Indazoles; D012694:Serine; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2