Design and Discovery of 2‑Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

Tankyrases (TNKSs) are poly­(ADP-ribose)­polymerases (PARPs) that are overexpressed in several clinical cancers. They regulate elongation of telomeres, regulate the <i>Wnt</i> system, and are essential for the function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been designed and identified as potent and selective TNKS inhibitors, some being more potent and selective than the lead inhibitor XAV939, with IC₅₀ = 3 nM vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the 4-position of the 2-phenyl group; electronic effects and H-bonding were irrelevant, but charge in the 4′-substituent must be avoided. Molecular modeling facilitated initial design of the compounds and rationalization of the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further development into anticancer drugs