title: ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer.
abstract: Colorectal cancer is one of the leading causes of cancer mortality in Western civilization. Studies have shown that colorectal cancer arises as a consequence of the modification of genes that regulate important cellular functions. Deregulation of the WNT and RAS/MAPK/PI3K signaling pathways has been shown to be important in the early stages of colorectal cancer development and progression. Krüppel-like factor 5 (KLF5) is a transcription factor that is highly expressed in the proliferating intestinal crypt epithelial cells. Previously, we showed that KLF5 is a mediator of RAS/MAPK and WNT signaling pathways under homeostatic conditions and that it promotes their tumorigenic functions during the development and progression of intestinal adenomas. Recently, using an ultrahigh-throughput screening approach we identified a number of novel small molecules that have the potential to provide therapeutic benefits for colorectal cancer by targeting KLF5 expression. In the current study, we show that an improved analogue of one of these screening hits, ML264, potently inhibits proliferation of colorectal cancer cells in vitro through modifications of the cell-cycle profile. Moreover, in an established xenograft mouse model of colon cancer, we demonstrate that ML264 efficiently inhibits growth of the tumor within 5 days of treatment. We show that this effect is caused by a significant reduction in proliferation and that ML264 potently inhibits the expression of KLF5 and EGR1, a transcriptional activator of KLF5. These findings demonstrate that ML264, or an analogue, may hold a promise as a novel therapeutic agent to curb the development and progression of colorectal cancer.
authors.affiliation: Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York.
authors.forename: Ainara
authors.initials: A
authors.lastname: Ruiz de Sabando
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: He
authors.affiliation: The Stony Brook Cancer Center, Stony Brook, New York.
authors.forename: Mónica
authors.initials: M
authors.lastname: García-Barros
authors.affiliation: Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York.
authors.forename: Julie
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology, Stony Brook University School of Medicine, Stony Brook, New York.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Shroyer
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bannister
authors.affiliation: Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York. Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony Brook, New York. Agnieszka.Bialkowska@stonybrookmedicine.edu Vincent.Yang@stonybrookmedicine.edu.
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Yang
authors.affiliation: Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York. Agnieszka.Bialkowska@stonybrookmedicine.edu Vincent.Yang@stonybrookmedicine.edu.
authors.forename: Agnieszka B
authors.initials: AB
authors.lastname: Bialkowska
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D015415:Biomarkers; D003499:Cyclic S-Oxides; D016213:Cyclins; C000611564:ML264 compound; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins