Structural highlights
Publication Abstract from PubMedHuman 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. para-Substituted 2-Phenyl-3,4-dihydroquinazolin-4-ones As Potent and Selective Tankyrase Inhibitors.,Haikarainen T, Koivunen J, Narwal M, Venkannagari H, Obaji E, Joensuu P, Pihlajaniemi T, Lehtio L ChemMedChem. 2013 Oct 15. doi: 10.1002/cmdc.201300337. PMID:24130191[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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This page was last modified 17:43, 21 December 2014.