Helmholtz Gemeinschaft


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. and Waaler, J. and Nkizinkiko, Y. and Ignatev, A. and Lazarow, K. and Lindemann, P. and Olsen, P.A. and Murthy, S. and Obaji, E. and Majouga, A.G. and Leonov, S. and von Kries, J.P. and Lehtiö, L. and 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

Repository Staff Only: item control page

Open Access
MDC Library