title: Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors.
abstract: Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.
authors.affiliation: Department of Chemistry Research and Discovery, ‡Department of Pharmacokinetics and Drug Metabolism, §Oncology Research, ∥Department of Molecular Structure, ⊥Bioassay and Profiling, and #Pharmaceutics, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Zihao
authors.initials: Z
authors.lastname: Hua
authors.forename: Howard
authors.initials: H
authors.lastname: Bregman
authors.forename: John L
authors.initials: JL
authors.lastname: Buchanan
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: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
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: Renee
authors.initials: R
authors.lastname: Emkey
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: Lisa
authors.initials: L
authors.lastname: Acquaviva
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dovey
authors.forename: Ankita
authors.initials: A
authors.lastname: Mishra
authors.forename: John
authors.initials: J
authors.lastname: Newcomb
authors.forename: Douglas
authors.initials: D
authors.lastname: Saffran
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: Mary
authors.initials: M
authors.lastname: Stanton
authors.forename: Cindy
authors.initials: C
authors.lastname: Wilson
authors.forename: Erin F
authors.initials: EF
authors.lastname: Dimauro
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D038501:Tankyrases