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

Nathubhai, Amit, Wood, P.J., Lloyd, M.D., Thompson, A.S. and Threadgill, M.D. (2013) Design and Discovery of 2‑Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases. ACS Medicinal Chemistry Letters, 4 (12). pp. 1173-1177. ISSN 1948-5875

[img] PDF
ACS Med Chem Lett 2013 4 1173-1177.pdf - Published Version
Restricted to Repository staff only

Download (4MB) | Request a copy

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.

Item Type: Article
Subjects: Sciences > Chemistry
Divisions: Health Sciences and Wellbeing Beacon > Drug Discovery and Application Workstream
Depositing User: Amit Nathubhai
Date Deposited: 10 Aug 2018 10:46
Last Modified: 10 Aug 2018 10:46
URI: http://sure.sunderland.ac.uk/id/eprint/9792

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year