title: Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis.
abstract: The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide's mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol (4) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide's inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: robert.mook@duke.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mook
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Xiu-Rong
authors.initials: XR
authors.lastname: Ren
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Hailan
authors.initials: H
authors.lastname: Piao
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Barak
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: H
authors.initials: H
authors.lastname: Kim Lyerly
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: w.chen@dm.duke.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D009534:Niclosamide / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D051153:Wnt Proteins; D051176:beta Catenin; D009534:Niclosamide; D000255:Adenosine Triphosphate
keywords: ATP; Cancer; Drug design; Mechanism; Niclosamide; Oxidative phosphorylation; Protonophore; Small molecule; Wnt signaling inhibitor; β-catenin