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Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

Paine, Helen A. ; Nathubhai, Amit ; Woon, Esther C.Y. ; Sunderland, Peter T. ; Wood, Pauline J. ; Mahon, Mary F. ; Lloyd, Matthew D. ; Thompson, Andrew S. ; Haikarainen, Teemu ; Narwal, Mohit ; Lehtiö, Lari ; Threadgill, Michael D.

Bioorganic & Medicinal Chemistry, 09/2015, Vol.23(17), pp.5891-5908 [Periódico revisado por pares]

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  • Título:
    Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro
  • Autor: Paine, Helen A. ; Nathubhai, Amit ; Woon, Esther C.Y. ; Sunderland, Peter T. ; Wood, Pauline J. ; Mahon, Mary F. ; Lloyd, Matthew D. ; Thompson, Andrew S. ; Haikarainen, Teemu ; Narwal, Mohit ; Lehtiö, Lari ; Threadgill, Michael D.
  • Assuntos: Cytokinins – Analysis ; Niacinamide – Analysis ; Nitriles – Analysis ; Crystal Structure – Analysis ; Telomeres – Analysis
  • É parte de: Bioorganic & Medicinal Chemistry, 09/2015, Vol.23(17), pp.5891-5908
  • Descrição: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/j.bmc.2015.06.061 Byline: Helen A. Paine (a), Amit Nathubhai (a), Esther C.Y. Woon (a,b), Peter T. Sunderland (a), Pauline J. Wood (a), Mary F. Mahon (c), Matthew D. Lloyd (a), Andrew S. Thompson (a), Teemu Haikarainen (d), Mohit Narwal (d), Lari LehtiAaAaAeA (d), Michael D. Threadgill [m.d.threadgill@bath.ac.u (a,*) Keywords Tankyrase; TNKS; Naphthyridinone; 7-Aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one; Crystal structure Abstract Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD.sup.+ as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/[beta]-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. Author Affiliation: (a) Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK (b) Department of Pharmacy, National University of Singapore, Block S4, Science Drive 4, Singapore 117543, Republic of Singapore (c) X-ray Crystallographic Suite, Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK (d) Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland * Corresponding author. Tel.: +44 1225 386840; fax: +44 1225 386114. Article History: Received 27 April 2015; Revised 24 June 2015; Accepted 25 June 2015
  • Idioma: Inglês

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