title: Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases.
abstract: 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.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Bath BA2 7AY, United Kingdom.
authors.forename: Amit
authors.initials: A
authors.lastname: Nathubhai
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Bath BA2 7AY, United Kingdom.
authors.forename: Pauline J
authors.initials: PJ
authors.lastname: Wood
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Bath BA2 7AY, United Kingdom.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lloyd
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Bath BA2 7AY, United Kingdom.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Thompson
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Bath BA2 7AY, United Kingdom.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Threadgill
keywords: PARP; Tankyrase; hydrophobic pocket; quinazolin-4-one; selectivity