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

Summary for 4BUX

• Entry DOI: 10.2210/pdb4bux/pdb
• Related: 4BU3 4BU5 4BU6 4BU7 4BU8 4BU9 4BUA 4BUD 4BUE 4BUF 4BUI 4BUS 4BUT 4BUU 4BUV 4BUW 4BUY
• Descriptor: TANKYRASE-2, ZINC ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: transferase, protein-ligand complex, diphtheria toxin like fold, adp-ribosylation, transferase-transferase inhibitor complex
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 55875.35

Authors

Haikarainen, T.,Narwal, M.,Lehtio, L. (deposition date: 2013-06-24, release date: 2013-10-30, Last modification date: 2023-12-20)

Primary citation

Haikarainen, T.,Koivunen, J.,Narwal, M.,Venkannagari, H.,Obaji, E.,Joensuu, P.,Pihlajaniemi, T.,Lehtio, L.
Para-Substituted 2-Phenyl-3,4-Dihydroquinazolin-4-Ones as Potent and Selective Tankyrase Inhibitors.
Chemmedchem, 8:1978-, 2013

PubMed 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.

PubMed: 24130191
DOI: 10.1002/CMDC.201300337

Experimental method

X-RAY DIFFRACTION (1.95 Å)