title: Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors.
abstract: Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors. These compounds exhibited good enzyme and cell potency as well as selectivity over other PARP isoforms. Co-crystal structures of these 2-aminopyridine oxazolidinones complexed to TNKS reveal an induced-pocket binding mode that does not involve interactions with the nicotinamide binding pocket. Oral dosing of lead compounds 3 and 4 resulted in significant effects on several Wnt-pathway biomarkers in a three day DLD-1 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: Angel
authors.initials: A
authors.lastname: Guzman-Perez
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: 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: 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: 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: 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: 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: Erin F
authors.initials: EF
authors.lastname: DiMauro
keywords: 2-aminopyridine oxazolidinone; PARP; Wnt pathway; cancer; tankyrase inhibitor