4BU5: Crystal structure of human tankyrase 2 in complex with 2-(4- hydroxyphenyl)-3,4-dihydroquinazolin-4-one

Citation:
Abstract
Human tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a set of highly potent tankyrase inhibitors based on a 2-phenyl-3,4-dihydroquinazolin-4-one scaffold. Substitutions at the para position of the scaffold's phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single-digit nanomolar potencies, and profiling against several human diphtheria-toxin-like ADP-ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X-ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2-phenyl-3,4-dihydroquinazolin-4-one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain.
PDB ID: 4BU5Download
MMDB ID: 114611
PDB Deposition Date: 2013/6/20
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 1.8  Å
Source Organism:
Similar Structures:
Biological Unit for 4BU5: monomeric; determined by author and by software (PISA)
Molecular Components in 4BU5
Label Count Molecule
Protein (1 molecule)
1
Tankyrase-2(Gene symbol: TNKS2)
Molecule annotation
Chemicals (6 molecules)
1
1
2
1
3
2
4
1
5
1
* Click molecule labels to explore molecular sequence information.

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