Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
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- 作者：Zihao Hua ; Howard Bregman ; John L. Buchanan ; Nagasree Chakka ; Angel Guzman-Perez ; Hakan Gunaydin ; Xin Huang ; Yan Gu ; Virginia Berry ; Jingzhou Liu ; Yohannes Teffera ; Liyue Huang ; Bryan Egge ; Renee Emkey ; Erin L. Mullady ; Steve Schneider ; Paul S. Andrews ; Lisa Acquaviva ; Jennifer Dovey ; Ankita Mishra ; John Newcomb ; Douglas Saffran ; Randy Serafino ; Craig A. Strathdee ; Susan M. Turci ; Mary Stanton ; Cindy Wilson ; Erin F. DiMauro
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：December 27, 2013
- 年：2013
- 卷：56
- 期：24
- 页码：10003-10015
- 全文大小：628K
- ISSN：1520-4804
文摘
Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting 尾-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound <b>8b> was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound <b>8b> leading to the identification of more potent and selective tankyrase inhibitors <b>22b> and <b>49b> with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.