Naro Yuta, Thomas Meryl, Stephens Matthew D, Connelly Colleen M, Deiters Alexander
University of Pittsburgh, Department of Chemistry, 219 Parkman Ave, Pittsburgh, PA 15260, United States.
North Carolina State University, Department of Chemistry, Campus Box 8204, Raleigh, NC 27695, United States.
Bioorg Med Chem Lett. 2015 Nov 1;25(21):4793-4796. doi: 10.1016/j.bmcl.2015.07.016. Epub 2015 Jul 17.
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.
微小RNA（miRNA）是约22个核苷酸的单链RNA分子，可负向调节基因表达。miRNA参与诸如发育、分化、增殖和存活等基本细胞过程。miRNA失调与多种人类疾病相关，最显著的是癌症。MicroRNA-21（miR-21）是一种公认的致癌miRNA，在多种人类癌症中显著过表达，因此使miR-21成为一个潜在的治疗靶点。在miR-21表达的控制下，使用基于荧光素酶的报告基因检测法，对超过300,000种化合物进行高通量筛选，发现了一类新的芳基酰胺类小分子miR-21抑制剂。构效关系（SAR）研究导致开发出四种芳基酰胺衍生物作为强效且选择性的miR-21抑制剂。通过qRT-PCR分析了HeLa细胞中各种miRNA的细胞内水平，揭示了对miR-21抑制相对于其他miRNA的特异性。此外，初步的作用机制研究提出了一种与先前报道的miR-21抑制剂不同的作用模式，从而为未来的研究提供了一种新的化学探针。
