title: Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA-Encoded Chemical Library.
abstract: We describe the synthesis and screening of a DNA-encoded chemical library containing 76230 compounds. In this library, sets of amines and carboxylic acids are directly linked producing encoded compounds with compact structures and drug-like properties. Affinity screening of this library yielded inhibitors of the potential pharmaceutical target tankyrase 1, a poly(ADP-ribose) polymerase. These compounds have drug-like characteristics, and the most potent hit compound (X066/Y469) inhibited tankyrase 1 with an IC50 value of 250 nM.
authors.affiliation: §Philochem AG, Libernstrasse 3, 8112 Otelfingen, Switzerland.
authors.forename: Florent
authors.initials: F
authors.lastname: Samain
authors.affiliation: ‡Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, 17177 Stockholm, Sweden.
authors.forename: Torun
authors.initials: T
authors.lastname: Ekblad
authors.affiliation: §Philochem AG, Libernstrasse 3, 8112 Otelfingen, Switzerland.
authors.forename: Gediminas
authors.initials: G
authors.lastname: Mikutis
authors.affiliation: ∥Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhong
authors.affiliation: †Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5, 8093 Zürich, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: †Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5, 8093 Zürich, Switzerland.|§Philochem AG, Libernstrasse 3, 8112 Otelfingen, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Nauer
authors.affiliation: †Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5, 8093 Zürich, Switzerland.
authors.forename: Davor
authors.initials: D
authors.lastname: Bajic
authors.affiliation: †Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5, 8093 Zürich, Switzerland.
authors.forename: Willy
authors.initials: W
authors.lastname: Decurtins
authors.affiliation: †Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5, 8093 Zürich, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Scheuermann
authors.affiliation: ∥Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: †Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5, 8093 Zürich, Switzerland.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hall
authors.affiliation: ∥Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Susanne
authors.initials: S
authors.lastname: Gräslund
authors.affiliation: ‡Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, 17177 Stockholm, Sweden.
authors.forename: Herwig
authors.initials: H
authors.lastname: Schüler
authors.affiliation: †Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5, 8093 Zürich, Switzerland.
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
authors.affiliation: †Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5, 8093 Zürich, Switzerland.
authors.forename: Raphael M
authors.initials: RM
authors.lastname: Franzini
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015723:Gene Library; D006801:Humans; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000588:Amines; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D038501:Tankyrases; C418109:TNKS protein, human