title: Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro.
abstract: Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD(+) as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/β-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Paine
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Amit
authors.initials: A
authors.lastname: Nathubhai
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK; Department of Pharmacy, National University of Singapore, Block S4, Science Drive 4, Singapore 117543, Republic of Singapore.
authors.forename: Esther C Y
authors.initials: EC
authors.lastname: Woon
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Sunderland
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Pauline J
authors.initials: PJ
authors.lastname: Wood
authors.affiliation: X-ray Crystallographic Suite, Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Mahon
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lloyd
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Thompson
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: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
authors.forename: Mohit
authors.initials: M
authors.lastname: Narwal
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 & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK. Electronic address: m.d.threadgill@bath.ac.uk.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Threadgill
mesh_terms: D001665:Binding Sites; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000737:chemistry*
chemical_list: D038501:Tankyrases
keywords: 7-Aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one; Crystal structure; Naphthyridinone; TNKS; Tankyrase