ml5b00251_si_001.pdf (267.12 kB)

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

Download (267.12 kB)
journal contribution
posted on 10.09.2015, 00:00 by Javier de Vicente, Parcharee Tivitmahaisoon, Pamela Berry, David R. Bolin, Daisy Carvajal, Wei He, Kuo-Sen Huang, Cheryl Janson, Lena Liang, Christine Lukacs, Ann Petersen, Hong Qian, Lin Yi, Yong Zhuang, Johannes C. Hermann
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.