8 research outputs found
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
Structure of TNKS2 ARTD domain.
<p>Acceptor and donor NAD<sup>+</sup> binding sites, including nicotinamide subsite (NI) and adenosine subsite (ADE) are labelled.</p
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
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 Tankyrase Inhibiting Flavones with Increased Potency and Isoenzyme Selectivity
Tankyrases
are ADP-ribosyltransferases that play key roles in various
cellular pathways, including the regulation of cell proliferation,
and thus, they are promising drug targets for the treatment of cancer.
Flavones have been shown to inhibit tankyrases and we report here
the discovery of more potent and selective flavone derivatives. Commercially
available flavones with single substitutions were used for structure–activity
relationship studies, and cocrystal structures of the 18 hit compounds
were analyzed to explain their potency and selectivity. The most potent
inhibitors were also tested in a cell-based assay, which demonstrated
that they effectively antagonize Wnt signaling. To assess selectivity,
they were further tested against a panel of homologous human ADP-ribosyltransferases.
The most effective compound, <b>22</b> (MN-64), showed 6 nM
potency against tankyrase 1, isoenzyme selectivity, and Wnt signaling
inhibition. This work forms a basis for rational development of flavones
as tankyrase inhibitors and guides the development of other structurally
related inhibitors
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 IC<sub>50</sub> 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 IC<sub>50</sub> 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