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


  • U.R. Anumala
  • J. Waaler
  • Y. Nkizinkiko
  • A. Ignatev
  • K. Lazarow
  • P. Lindemann
  • P.A. Olsen
  • S. Murthy
  • E. Obaji
  • A.G. Majouga
  • S. Leonov
  • J.P. von Kries
  • L. Lehtiö
  • S. Krauss
  • M. Nazaré


  • Journal of Medicinal Chemistry


  • J Med Chem 60 (24): 10013-10025


  • 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.