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ACS Med Chem Lett. 2013 Oct 15;4(12):1173-7. doi: 10.1021/ml400260b. eCollection 2013 Dec 12.

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

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Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Bath BA2 7AY, United Kingdom.


Tankyrases (TNKSs) are poly(ADP-ribose)polymerases (PARPs) that are overexpressed in several clinical cancers. They regulate elongation of telomeres, regulate the Wnt 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.


PARP; Tankyrase; hydrophobic pocket; quinazolin-4-one; selectivity

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