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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, 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

Item Type: Article


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.

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Depositing User: Amit Nathubhai


Item ID: 9791
Identification Number:
ISSN: 0968-0896
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Date Deposited: 10 Aug 2018 10:03
Last Modified: 18 Dec 2019 16:07


Author: H.A. Paine
Author: Amit Nathubhai
Author: E.C.Y. Woon
Author: P.T. Sunderland
Author: P.J. Wood
Author: M.F. Mahon
Author: M.D. Lloyd
Author: A.S. Thompson
Author: T. Haikarainen
Author: M. Narwal
Author: L. Lehtiö
Author: M.D. Threadgill

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Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences


Sciences > Chemistry

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