title: para-Substituted 2-phenyl-3,4-dihydroquinazolin-4-ones as potent and selective tankyrase inhibitors.
abstract: Human tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a set of highly potent tankyrase inhibitors based on a 2-phenyl-3,4-dihydroquinazolin-4-one scaffold. Substitutions at the para position of the scaffold's phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single-digit nanomolar potencies, and profiling against several human diphtheria-toxin-like ADP-ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X-ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2-phenyl-3,4-dihydroquinazolin-4-one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain.
authors.affiliation: Department of Biochemistry and Biocenter Oulu, 90014 University of Oulu, PO Box 3000 Oulu (Finland).
authors.forename: Teemu
authors.initials: T
authors.lastname: Haikarainen
authors.forename: Jarkko
authors.initials: J
authors.lastname: Koivunen
authors.forename: Mohit
authors.initials: M
authors.lastname: Narwal
authors.forename: Harikanth
authors.initials: H
authors.lastname: Venkannagari
authors.forename: Ezeogo
authors.initials: E
authors.lastname: Obaji
authors.forename: Päivi
authors.initials: P
authors.lastname: Joensuu
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.forename: Lari
authors.initials: L
authors.lastname: Lehtiö
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D011485:Protein Binding; D052999:Quinazolinones / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D055672:Static Electricity; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D052999:Quinazolinones; D038501:Tankyrases; C418109:TNKS protein, human
keywords: Wnt signaling; inhibitors; structural biology; structure-activity relationships; tankyrase