title: Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics.
abstract: Diphtheria toxin-like ADP-ribosyltransferases catalyse a posttranslational modification, ADP-ribosylation and form a protein family of 17 members in humans. Two of the family members, tankyrases 1 and 2, are involved in several cellular processes including mitosis and Wnt/β-catenin signalling pathway. They are often over-expressed in cancer cells and have been linked with the survival of cancer cells making them potential therapeutic targets. In this study, we identified nine tankyrase inhibitors through virtual and in vitro screening. Crystal structures of tankyrase 2 with the compounds showed that they bind to the nicotinamide binding site of the catalytic domain. Based on the co-crystal structures we designed and synthesized a series of tetrahydroquinazolin-4-one and pyridopyrimidin-4-one analogs and were subsequently able to improve the potency of a hit compound almost 100-fold (from 11 μM to 150 nM). The most potent compounds were selective towards tankyrases over a panel of other human ARTD enzymes. They also inhibited Wnt/β-catenin pathway in a cell-based reporter assay demonstrating the potential usefulness of the identified new scaffolds for further development.
authors.affiliation: Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, PO Box 5400, FIN-90014 Oulu, Finland.
authors.forename: Yves
authors.initials: Y
authors.lastname: Nkizinkiko
authors.affiliation: Department of Pharmacy at Birla Institute of Technology and Science-Pilani, Hyderabad campus, Hyderabad 500078, India.
authors.forename: B V S
authors.initials: BVS
authors.lastname: Suneel Kumar
authors.affiliation: Department of Pharmacy at Birla Institute of Technology and Science-Pilani, Hyderabad campus, Hyderabad 500078, India.
authors.forename: Variam Ullas
authors.initials: VU
authors.lastname: Jeankumar
authors.affiliation: Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, PO Box 5400, FIN-90014 Oulu, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Haikarainen
authors.affiliation: Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, PO Box 5400, FIN-90014 Oulu, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Koivunen
authors.affiliation: Department of Pharmacy at Birla Institute of Technology and Science-Pilani, Hyderabad campus, Hyderabad 500078, India.
authors.forename: Chanduri
authors.initials: C
authors.lastname: Madhuri
authors.affiliation: Department of Pharmacy at Birla Institute of Technology and Science-Pilani, Hyderabad campus, Hyderabad 500078, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, PO Box 5400, FIN-90014 Oulu, Finland.
authors.forename: Harikanth
authors.initials: H
authors.lastname: Venkannagari
authors.affiliation: Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, PO Box 5400, FIN-90014 Oulu, Finland.
authors.forename: Ezeogo
authors.initials: E
authors.lastname: Obaji
authors.affiliation: Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, PO Box 5400, FIN-90014 Oulu, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.affiliation: Department of Pharmacy at Birla Institute of Technology and Science-Pilani, Hyderabad campus, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.affiliation: Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, PO Box 5400, FIN-90014 Oulu, Finland. Electronic address: lari.lehtio@oulu.fi.
authors.forename: Lari
authors.initials: L
authors.lastname: Lehtiö
mesh_terms: D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D018716:Molecular Mimicry; D009536:Niacinamide / Q000737:chemistry*; D011799:Quinazolines / Q000737:chemistry; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D009536:Niacinamide; C437334:TNKS2 protein, human; D038501:Tankyrases
keywords: Cancer; Inhibition; Poly(ADP-ribose)polymerase; Protein crystallography; Tankyrase; Virtual screening; Wnt-signalling