title: Development and structural analysis of adenosine site binding tankyrase inhibitors.
abstract: Tankyrases 1 and 2, the specialized members of the ARTD protein family, are druggable biotargets whose inhibition may have therapeutic potential against cancer, metabolic disease, fibrotic disease, fibrotic wound healing and HSV viral infections. We have previously identified a novel tankyrase inhibitor scaffold, JW55, and showed that it reduces mouse colon adenoma formation in vivo. Here we expanded the scaffold and profiled the selectivity of the compounds against a panel of human ARTDs. The scaffold also enables a fine modulation of selectivity towards either tankyrase 1 or tankyrase 2. In order to get insight about the binding mode of the inhibitors, we solved crystal structures of the compounds in complex with tankyrase 2. The compounds bind to the adenosine pocket of the catalytic domain and cause changes in the protein structure that are modulated by the chemical modifications of the compounds. The structural analysis allows further rational development of this compound class as a potent and selective tankyrase inhibitor.
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Haikarainen
authors.affiliation: Unit for Cell Signaling, Institute of Medical Microbiology, Oslo University Hospital, Gaustadalleen 34, 0372 Oslo, Norway.
authors.forename: Jo
authors.initials: J
authors.lastname: Waaler
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ignatev
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Yves
authors.initials: Y
authors.lastname: Nkizinkiko
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Harikanth
authors.initials: H
authors.lastname: Venkannagari
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Ezeogo
authors.initials: E
authors.lastname: Obaji
authors.affiliation: Unit for Cell Signaling, Institute of Medical Microbiology, Oslo University Hospital, Gaustadalleen 34, 0372 Oslo, Norway. Electronic address: stefan.krauss@rr-research.no.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krauss
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland. Electronic address: lari.lehtio@oulu.fi.
authors.forename: Lari
authors.initials: L
authors.lastname: Lehtiö
mesh_terms: D000241:Adenosine / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D062366:para-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000241:Adenosine; D000970:Antineoplastic Agents; D038501:Tankyrases; D062366:para-Aminobenzoates; C000613569:JW55 compound; C437334:TNKS2 protein, human; C418109:TNKS protein, human
keywords: ARTD; PARP; Small-molecule; Tankyrase; Tankyrase inhibitor; WNT inhibitor; WNT signaling