title: SRI36160 is a specific inhibitor of Wnt/β-catenin signaling in human pancreatic and colorectal cancer cells.
abstract: Activation of Wnt/β-catenin signaling is associated with pancreatic and colorectal cancer, among others. To-date, there are no FDA-approved small molecule Wnt/β-catenin inhibitors and many past efforts resulted in compounds with undesirable off-target effects. We recently identified a series of benzimidazole analogs as potent inhibitors of Wnt/β-catenin signaling. Here, we show that the lead compound SRI36160 displayed selective Wnt inhibition and potent antiproliferative activity in pancreatic and colorectal cancer cells. Moreover, SRI36160 had no effect on STAT3 and mTORC1 signaling in pancreatic and colorectal cancer cells, and was not effective in inhibiting proliferation of non-cancerous cells. Our findings suggest that this series of benzimidazole analogs presents a novel approach for the treatment of Wnt-dependent cancers such as colorectal and pancreatic cancer.
authors.affiliation: Drug Discovery Division, Southern Research, 2000 Ninth Avenue South, Birmingham, AL 35255, USA. Electronic address: yli@southernresearch.org.
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Patsy G
authors.initials: PG
authors.lastname: Oliver
authors.affiliation: Drug Discovery Division, Southern Research, 2000 Ninth Avenue South, Birmingham, AL 35255, USA.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Lu
authors.affiliation: Drug Discovery Division, Southern Research, 2000 Ninth Avenue South, Birmingham, AL 35255, USA.
authors.forename: Vibha
authors.initials: V
authors.lastname: Pathak
authors.affiliation: Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Sivaram
authors.initials: S
authors.lastname: Sridharan
authors.affiliation: Drug Discovery Division, Southern Research, 2000 Ninth Avenue South, Birmingham, AL 35255, USA.
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Augelli-Szafran
authors.affiliation: Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
authors.affiliation: Drug Discovery Division, Southern Research, 2000 Ninth Avenue South, Birmingham, AL 35255, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Suto
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000502:physiology; D051379:Mice; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060509:Wnt3A Protein / Q000502:physiology; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D001562:Benzimidazoles; C495270:CTNNB1 protein, human; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C000621687:SRI36160; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060509:Wnt3A Protein; D051176:beta Catenin
keywords: Benzimidazole; Drug discovery; Niclosamide; Targeted therapy; Wnt signaling