title: 2-Phenylamino-6-cyano-1H-benzimidazole-based isoform selective casein kinase 1 gamma (CK1γ) inhibitors.
abstract: Screening of the Amgen compound library led to the identification of 2-phenylamino-6-cyano-1H-benzimidazole 1a as a potent CK1 gamma inhibitor with excellent kinase selectivity and unprecedented CK1 isoform selectivity. Further structure-based optimization of this series resulted in the discovery of 1h which possessed good enzymatic and cellular potency, excellent CK1 isoform and kinase selectivity, and acceptable pharmacokinetic properties.
authors.affiliation: Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA. zihao.hua@amgen.com
authors.forename: Zihao
authors.initials: Z
authors.lastname: Hua
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Howard
authors.initials: H
authors.lastname: Bregman
authors.forename: Nagasree
authors.initials: N
authors.lastname: Chakka
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: Jon
authors.initials: J
authors.lastname: Goldstein
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.forename: Hongbing
authors.initials: H
authors.lastname: Huang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mercede
authors.forename: John
authors.initials: J
authors.lastname: Newcomb
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Susan M
authors.initials: SM
authors.lastname: Turci
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.forename: Cindy
authors.initials: C
authors.lastname: Wilson
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Martin
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D047389:Casein Kinase I / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D051176:beta Catenin / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D047389:Casein Kinase I