4L0I: Tankyrase 2 catalytic domain in complex with ethyl 4-(4-oxo-4H-chromen-2-yl)benzoate

Citation:
Abstract
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, 22 (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.
PDB ID: 4L0IDownload
MMDB ID: 114736
PDB Deposition Date: 2013/5/31
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 4L0I: dimeric; determined by author and by software (PISA)
Molecular Components in 4L0I
Label Count Molecule
Proteins (2 molecules)
1
Tankyrase-2(Gene symbol: TNKS2)
Molecule annotation
1
Tankyrase-2(Gene symbol: TNKS2)
Molecule annotation
Chemicals (4 molecules)
1
1
2
1
3
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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