title: Aryl amide small-molecule inhibitors of microRNA miR-21 function.
abstract: MicroRNAs (miRNAs) are single stranded RNA molecules of ∼22 nucleotides that negatively regulate gene expression. MiRNAs are involved in fundamental cellular processes, such as development, differentiation, proliferation, and survival. MiRNA misregulation has been linked to various human diseases, most notably cancer. MicroRNA-21 (miR-21), a well-established oncomiR, is significantly overexpressed in many types of human cancers, thus rendering miR-21 a potential therapeutic target. Using a luciferase-based reporter assay under the control of miR-21 expression, a high-throughput screen of >300,000 compounds led to the discovery of a new aryl amide class of small-molecule miR-21 inhibitors. Structure-activity relationship (SAR) studies resulted in the development of four aryl amide derivatives as potent and selective miR-21 inhibitors. The intracellular levels of various miRNAs in HeLa cells were analyzed by qRT-PCR revealing specificity for miR-21 inhibition over other miRNAs. Additionally, preliminary mechanism of action studies propose a different mode of action compared to previously reported miR-21 inhibitors, thus affording a new chemical probe for future studies.
authors.affiliation: University of Pittsburgh, Department of Chemistry, 219 Parkman Ave, Pittsburgh, PA 15260, United States.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Naro
authors.affiliation: University of Pittsburgh, Department of Chemistry, 219 Parkman Ave, Pittsburgh, PA 15260, United States.
authors.forename: Meryl
authors.initials: M
authors.lastname: Thomas
authors.affiliation: North Carolina State University, Department of Chemistry, Campus Box 8204, Raleigh, NC 27695, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Stephens
authors.affiliation: North Carolina State University, Department of Chemistry, Campus Box 8204, Raleigh, NC 27695, United States.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Connelly
authors.affiliation: University of Pittsburgh, Department of Chemistry, 219 Parkman Ave, Pittsburgh, PA 15260, United States. Electronic address: deiters@pitt.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Deiters
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D054852:Small Molecule Libraries
keywords: Cancer; Gene regulation; MicroRNA; Post-transcriptional regulation; Small-molecule inhibitors; miR-21