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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.

SUBMITTER: Nathubhai A

PROVIDER: S-EPMC4027532 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Nathubhai Amit A Wood Pauline J PJ Lloyd Matthew D MD Thompson Andrew S AS Threadgill Michael D MD

ACS medicinal chemistry letters 20131015 12

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 ...[more]

PMID: 24900625

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