Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach

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 IC50 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.