title: Highly Potent and Isoform Selective Dual Site Binding Tankyrase/Wnt Signaling Inhibitors That Increase Cellular Glucose Uptake and Have Antiproliferative Activity.
abstract: Compounds 13 and 14 were evaluated against 11 PARP isoforms to reveal that both 13 and 14 were more potent and isoform selective toward inhibiting tankyrases (TNKSs) than the "standard" inhibitor 1 (XAV939)5, i.e., IC50= 100 pM vs TNKS2 and IC50= 6.5 μM vs PARP1 for 14. In cellular assays, 13 and 14 inhibited Wnt-signaling, enhanced insulin-stimulated glucose uptake, and inhibited the proliferation of DLD-1 colorectal adenocarcinoma cells to a greater extent than 1.
authors.affiliation: Drug and Target Discovery, Department of Pharmacy and Pharmacology, University of Bath , Claverton Down, Bath, Somerset BA2 7AY, U. K.
authors.forename: Amit
authors.identifier: 0000-0003-3686-2799
authors.initials: A
authors.lastname: Nathubhai
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu , PO Box 5400, 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, 90014 Oulu, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Koivunen
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu , PO Box 5400, 90014 Oulu, Finland.
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Murthy
authors.affiliation: Department of Biology and Biochemistry, University of Bath , Bath BA2 7AY, U. K.
authors.forename: Françoise
authors.initials: F
authors.lastname: Koumanov
authors.affiliation: Drug and Target Discovery, Department of Pharmacy and Pharmacology, University of Bath , Claverton Down, Bath, Somerset BA2 7AY, U. K.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lloyd
authors.affiliation: Department of Biology and Biochemistry, University of Bath , Bath BA2 7AY, U. K.
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Holman
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu , PO Box 5400, 90014 Oulu, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.affiliation: Department of Biology and Biochemistry, University of Bath , Bath BA2 7AY, U. K.
authors.forename: David
authors.initials: D
authors.lastname: Tosh
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu , PO Box 5400, 90014 Oulu, Finland.
authors.forename: Lari
authors.initials: L
authors.lastname: Lehtiö
authors.affiliation: Drug and Target Discovery, Department of Pharmacy and Pharmacology, University of Bath , Claverton Down, Bath, Somerset BA2 7AY, U. K.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Threadgill
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D052999:Quinazolinones / Q000138:chemical synthesis / Q000494:pharmacology*; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: C000620978:2-(3-oxo-3-(4-((quinolin-8-yl)aminocarbonyl)phenylamino)propyl)quinazolin-4-one; C000620979:8-methyl-2-(3-oxo-3-(4-((quinolin-8-yl)aminocarbonyl)phenylamino)propyl)quinazolin-4-one; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020033:Protein Isoforms; D052999:Quinazolinones; C544261:XAV939; C437334:TNKS2 protein, human; D038501:Tankyrases; D005947:Glucose