para‐Substituted 2‐Phenyl‐3,4‐dihydroquinazolin‐4‐ones As Potent and Selective Tankyrase Inhibitors

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.