title: Small molecule modulators of Wnt/β-catenin signaling.
abstract: 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/β-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/β-catenin signaling and the discovery of potent and selective modulators to treat human disease.
authors: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. robert.mook@duke.edu
authors: Robert A
authors: RA
authors: Mook
authors: Minyong
authors: M
authors: Chen
authors: Jiuyi
authors: J
authors: Lu
authors: Larry S
authors: LS
authors: Barak
authors: H Kim
authors: HK
authors: Lyerly
authors: Wei
authors: W
authors: Chen
mesh_terms: D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D009534:Niclosamide / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D054852:Small Molecule Libraries; D051176:beta Catenin; D009534:Niclosamide