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Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors.

ABSTRACT: Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors. These compounds exhibited good enzyme and cell potency as well as selectivity over other PARP isoforms. Co-crystal structures of these 2-aminopyridine oxazolidinones complexed to TNKS reveal an induced-pocket binding mode that does not involve interactions with the nicotinamide binding pocket. Oral dosing of lead compounds 3 and 4 resulted in significant effects on several Wnt-pathway biomarkers in a three day DLD-1 mouse tumor PD model.

SUBMITTER: Huang H 

PROVIDER: S-EPMC4027438 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors.

Huang Hongbing H   Guzman-Perez Angel A   Acquaviva Lisa L   Berry Virginia V   Bregman Howard H   Dovey Jennifer J   Gunaydin Hakan H   Huang Xin X   Huang Liyue L   Saffran Doug D   Serafino Randy R   Schneider Steve S   Wilson Cindy C   DiMauro Erin F EF  

ACS medicinal chemistry letters 20131021 12

Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors. These compounds exhibited good enzyme and cell potency as well as selectivity over other PARP isoforms. Co-crystal structures of these 2-am  ...[more]

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