title: Discovery of novel, induced-pocket binding oxazolidinones as potent, selective, and orally bioavailable tankyrase inhibitors.
abstract: Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates β-catenin concentrations, resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of β-catenin-mediated transcription and inhibit tumorigenesis. Compound 1 is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and molecular modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (39, 40).
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. hbregman@amgen.com
authors.forename: Howard
authors.initials: H
authors.lastname: Bregman
authors.forename: Nagasree
authors.initials: N
authors.lastname: Chakka
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Virginia
authors.initials: V
authors.lastname: Berry
authors.forename: Jingzhou
authors.initials: J
authors.lastname: Liu
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.forename: Liyue
authors.initials: L
authors.lastname: Huang
authors.forename: Bryan
authors.initials: B
authors.lastname: Egge
authors.forename: Erin L
authors.initials: EL
authors.lastname: Mullady
authors.forename: Steve
authors.initials: S
authors.lastname: Schneider
authors.forename: Paul S
authors.initials: PS
authors.lastname: Andrews
authors.forename: Ankita
authors.initials: A
authors.lastname: Mishra
authors.forename: John
authors.initials: J
authors.lastname: Newcomb
authors.forename: Randy
authors.initials: R
authors.lastname: Serafino
authors.forename: Craig A
authors.initials: CA
authors.lastname: Strathdee
authors.forename: Susan M
authors.initials: SM
authors.lastname: Turci
authors.forename: Cindy
authors.initials: C
authors.lastname: Wilson
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors*
chemical_list: C582913:1-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohexyl)-4-fluoro-2-oxo-2,3-dihydro-1H-benzo(d)imidazole-5-carbonitrile; C582912:1-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)cyclohexyl)-6-fluoro-2-oxo-2,3-dihydro-1H-benzo(d)imidazole-5-carbonitrile; D001562:Benzimidazoles; D023303:Oxazolidinones; D038501:Tankyrases; C498822:Tnks protein, mouse