期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 23, 期 7, 页码 2187-2191出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.01.101
关键词
Wnt signaling inhibitor; Wnt signaling activator; Small molecule; Mechanism of action; Target identification; Niclosamide
资金
- Pediatric Brain Tumor Foundation [5R01 CA113656-03]
- Clinical Oncology Research Center [5K12-CA100639-08]
- NIH
- NSF
- NC Biotechnology Center
- Duke University
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.
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