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Discovery of a novel series of tankyrase inhibitors by a hybridization approach

Item Type:Article
Title:Discovery of a novel series of tankyrase inhibitors by a hybridization approach
Creators Name:Anumala, U.R., Waaler, J., Nkizinkiko, Y., Ignatev, A., Lazarow, K., Lindemann, P., Olsen, P.A., Murthy, S., Obaji, E., Majouga, A.G., Leonov, S., von Kries, J.P., Lehtiö, L., Krauss, S. and Nazaré, M.
Abstract:A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC(50) values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker.
Keywords:Biological Availability, Drug Design, Enzyme Inhibitors, Inbred BALB C Mice, Inhibitory Concentration 50, Oral Administration, Poly(ADP-ribose) Polymerase Inhibitors, Preclinical Drug Evaluation, Sprague-Dawley Rats, Synthetic Chemistry Techniques, Tankyrases, X-Ray Crystallography, Xenograft Model Antitumor Assays, Animals, Dogs, Mice, Rats
Source:Journal of Medicinal Chemistry
Publisher:American Chemical Society
Page Range:10013-10025
Date:28 December 2017
Official Publication:https://doi.org/10.1021/acs.jmedchem.7b00883
PubMed:View item in PubMed

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