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Fragment-Based Drug Design of Novel Pyranopyridones as Cell Active and Orally Bioavailable Tankyrase Inhibitors.

ABSTRACT: Tankyrase activity has been linked to the regulation of intracellular axin levels, which have been shown to be crucial for the Wnt pathway. Deregulated Wnt signaling is important for the genesis of many diseases including cancer. We describe herein the discovery and development of a new series of tankyrase inhibitors. These pyranopyridones are highly active in various cell-based assays. A fragment/structure based optimization strategy led to a compound with good pharmacokinetic properties that is suitable for in vivo studies and further development.

SUBMITTER: de Vicente J

PROVIDER: S-EPMC4569882 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Fragment-Based Drug Design of Novel Pyranopyridones as Cell Active and Orally Bioavailable Tankyrase Inhibitors.

de Vicente Javier J Tivitmahaisoon Parcharee P Berry Pamela P Bolin David R DR Carvajal Daisy D He Wei W Huang Kuo-Sen KS Janson Cheryl C Liang Lena L Lukacs Christine C Petersen Ann A Qian Hong H Yi Lin L Zhuang Yong Y Hermann Johannes C JC

ACS medicinal chemistry letters 20150804 9

Tankyrase activity has been linked to the regulation of intracellular axin levels, which have been shown to be crucial for the Wnt pathway. Deregulated Wnt signaling is important for the genesis of many diseases including cancer. We describe herein the discovery and development of a new series of tankyrase inhibitors. These pyranopyridones are highly active in various cell-based assays. A fragment/structure based optimization strategy led to a compound with good pharmacokinetic properties that i ...[more]

PMID: 26396691

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