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

Paine, H.A., Nathubhai, Amit, Woon, E.C.Y., Sunderland, P.T., Wood, P.J., Mahon, M.F., Lloyd, M.D., Thompson, A.S., Haikarainen, T., Narwal, M., Lehtiö, L. and Threadgill, M.D. (2015) Exploration of the nicotinamide-binding site of the tankyrases,identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro. Bioorganic & Medicinal Chemistry, 23. pp. 5891-5908. ISSN 0968-0896

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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/b-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 parasubstituents 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.

Item Type: Article
Subjects: Sciences > Chemistry
Divisions: Health Sciences and Wellbeing Beacon > Drug Discovery and Application Workstream
Depositing User: Amit Nathubhai
Date Deposited: 10 Aug 2018 10:03
Last Modified: 10 Aug 2018 10:03
URI: http://sure.sunderland.ac.uk/id/eprint/9791

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