2 research outputs found
Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors
Tankyrases, an enzyme subfamily of
human poly(ADP-ribosyl)polymerases,
are potential drug targets especially against cancer. We have evaluated
inhibition of tankyrases by known PARP inhibitors and report five
cocrystal structures of the most potent compounds in complex with
human tankyrase 2. The inhibitors include the small general PARP inhibitors
Phenanthridinone, PJ-34, and TIQ-A as well as the more advanced inhibitors
EB-47 and rucaparib. The compounds anchor to the nicotinamide subsite
of tankyrase 2. Crystal structures reveal flexibility of the ligand
binding site with implications for drug development against tankyrases
and other ADP-ribosyltransferases. EB-47 mimics the substrate NAD<sup>+</sup> and extends from the nicotinamide to the adenosine subsite.
The clinical ARTD1 inhibitor candidate rucaparib was the most potent
tankyrase inhibitor identified (24 and 14 nM for tankyrases), which
indicates that inhibition of tankyrases would affect the cellular
responses of this compound
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