Design and discovery of 2‑arylquinazolin-4-ones as potent and selective inhibitors of tankyrases

Amit Nathubhai, Pauline J. Wood, Matthew D. Lloyd, Andrew S. Thompson, Michael D. Threadgill

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1173-1177
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume4
Issue number12
Early online date15 Oct 2013
DOIs
Publication statusPublished - 12 Dec 2013

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