Small molecule modulators of Wnt/β-catenin signaling

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Mook, Robert A., Jr.¹  Chen, Minyong¹  Lu, Jiuyi¹  Barak, Larry S.²  Lyerly, H. Kim³  Chen, Wei¹ 

[1] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[2] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA

[3] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA

关键词: Wnt signaling inhibitor;    Wnt signaling activator;    Small molecule;    Mechanism of action;    Target identification;    Niclosamide;   

DOI  :  10.1016/j.bmcl.2013.01.101

来源: Elsevier

【 摘 要 】

The Wnt signal transduction pathway is dysregulated in many highly prevalent diseases, including cancer. Unfortunately, drug discovery efforts have been hampered by the paucity of targets and drug-like lead molecules amenable to drug discovery. Recently, we reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/beta-catenin signaling by a unique mechanism, though the target responsible remains unknown. We interrogated the mechanism and structure-activity relationships to understand drivers of potency and to assist target identification efforts. We found inhibition of Wnt signaling by Niclosamide appears unique among the structurally-related anthelmintic agents tested and found the potency and functional response was dependent on small changes in the chemical structure of Niclosamide. Overall, these findings support efforts to identify the target of Niclosamide inhibition of Wnt/beta-catenin signaling And the discovery of potent and selective modulators to treat human disease. (C) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

Free