title: Structure-activity relationships of 2-arylquinazolin-4-ones as highly selective and potent inhibitors of the tankyrases.
abstract: Tankyrases (TNKSs), members of the PARP (Poly(ADP-ribose)polymerases) superfamily of enzymes, have gained interest as therapeutic drug targets, especially as they are involved in the regulation of Wnt signalling. A series of 2-arylquinazolin-4-ones with varying substituents at the 8-position was synthesised. An 8-methyl group (compared to 8-H, 8-OMe, 8-OH), together with a 4'-hydrophobic or electron-withdrawing group, provided the most potency and selectivity towards TNKSs. Co-crystal structures of selected compounds with TNKS-2 revealed that the protein around the 8-position is more hydrophobic in TNKS-2 compared to PARP-1/2, rationalising the selectivity. The NAD(+)-binding site contains a hydrophobic cavity which accommodates the 2-aryl group; in TNKS-2, this has a tunnel to the exterior but the cavity is closed in PARP-1. 8-Methyl-2-(4-trifluoromethylphenyl)quinazolin-4-one was identified as a potent and selective inhibitor of TNKSs and Wnt signalling. This compound and analogues could serve as molecular probes to study proliferative signalling and for development of inhibitors of TNKSs as drugs.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK. Electronic address: a.nathubhai@bath.ac.uk.
authors.forename: Amit
authors.initials: A
authors.lastname: Nathubhai
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Haikarainen
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK.
authors.forename: Penelope C
authors.initials: PC
authors.lastname: Hayward
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Muñoz-Descalzo
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Thompson
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lloyd
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Lari
authors.initials: L
authors.lastname: Lehtiö
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Threadgill
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D052999:Quinazolinones; C061339:4-hydroxyquinazoline; D038501:Tankyrases
keywords: 2-Arylquinazolin-4-one; Hydrophobic cavity; PARP; Tankyrase; Wnt