期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 21, 页码 4793-4796出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.07.016
关键词
miR-21; MicroRNA; Small-molecule inhibitors; Cancer; Gene regulation; Post-transcriptional regulation
资金
- American Cancer Society [120130-RSG-11-066-01-RMC]
MicroRNAs (miRNAs) are single stranded RNA molecules of similar to 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. (C) 2015 Elsevier Ltd. All rights reserved.
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