4BUX: Crystal Structure Of Human Tankyrase 2 In Complex With 3-(( 4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)methyl) Imidazolidine-2,4-dione

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: 4BUXDownload
MMDB ID: 114626
PDB Deposition Date: 2013/6/24
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 1.95  Å
Source Organism:
Similar Structures:
Biological Unit for 4BUX: monomeric; determined by author and by software (PISA)
Molecular Components in 4BUX
Label Count Molecule
Protein (1 molecule)
Tankyrase-2(Gene symbol: TNKS2)
Molecule annotation
Chemicals (5 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB