title: Structure-Based Design of Potent and Selective CK1γ Inhibitors.
abstract: Aberrant activation of the Wnt pathway is believed to drive the development and growth of some cancers. The central role of CK1γ in Wnt signal transduction makes it an attractive target for the treatment of Wnt-pathway dependent cancers. We describe a structure-based approach that led to the discovery of a series of pyridyl pyrrolopyridinones as potent and selective CK1γ inhibitors. These compounds exhibited good enzyme and cell potency, as well as selectivity against other CK1 isoforms. A single oral dose of compound 13 resulted in significant inhibition of LRP6 phosphorylation in a mouse tumor PD model.
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Huang
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Acquaviva
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Virginia
authors.initials: V
authors.lastname: Berry
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Howard
authors.initials: H
authors.lastname: Bregman
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Nagasree
authors.initials: N
authors.lastname: Chakka
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Connor
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dovey
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Oleg
authors.initials: O
authors.lastname: Epstein
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Grubinska
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Jon
authors.initials: J
authors.lastname: Goldstein
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Zihao
authors.initials: Z
authors.lastname: Hua
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Liyue
authors.initials: L
authors.lastname: Huang
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Human
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Long
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: John
authors.initials: J
authors.lastname: Newcomb
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Doug
authors.initials: D
authors.lastname: Saffran
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Randy
authors.initials: R
authors.lastname: Serafino
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Strathdee
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Jin
authors.initials: J
authors.lastname: Tang
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Turci
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: White
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Violeta
authors.initials: V
authors.lastname: Yu
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Cindy
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Departments of Medicinal Chemistry; Pharmacokinetics and Drug Metabolism; Oncology Research; and Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Martin
keywords: CK1γ; Wnt pathway; cancer; pyridyl pyrrolopyridinone