Potency of WIKI4 against TNKS1.

<p>The <i>in vitro</i> dose response curves were measured three times with a fluorescence-based homogenous activity assay.</p

Structure of TNKS2 ARTD domain.

<p>Acceptor and donor NAD⁺ binding sites, including nicotinamide subsite (NI) and adenosine subsite (ADE) are labelled.</p

Profiling of inhibitor selectivity.

<p>The selectivity of WIKI4 against 8 ARTDs polymerases was measured at 10 µM concentration. XAV939 and IWR-1 were used as controls.</p

Binding of WIKI4 to TNKS2.

<p>a) An overview of TNKS2 structure showing the binding site of WIKI4 (lilac) and XAV939 (dark purple) (pdb accession code 3KR8). b) Comparison of apo TNKS2 structure (pink) (pdb accession code 3KR7) and WIKI4 (turquoise) bound structure of TNKS2. c) Surface electrostatic presentation of WIKI4 binding site. Positive (surface potential charge above 0.25 V) and negative (surface potential charge below −0.25 V) electrostatic regions are colored blue and red, respectively.</p

Conditions used for the profiling of the inhibitors against human ARTDs.

<p>Conditions used for the profiling of the inhibitors against human ARTDs.</p

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 <b>16</b> 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

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 <b>16</b> 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