Small molecule inhibition of microRNA-21 expression reduces cell viability and microtumor formation.

MicroRNAs (miRNAs) are short, non-coding RNA molecules estimated to regulate expression of a large number of protein-coding genes and are implicated in a variety of biological processes such as development, differentiation, proliferation, and cell survival. Dysregulation of miRNAs has been attributed to the onset and progression of various human diseases, including cancer. MicroRNA-21 (miR-21), one of the most established oncogenic miRNAs, is found to be upregulated in a wide range of cancers making it an attractive therapeutic target. Employment of a luciferase-based live-cell reporter assay in a high-throughput screen of >300,000 small molecules led to the discovery of a new class of ether-amide miR-21 inhibitors. Following a structure-activity relationship study, an optimized lead molecule was found to inhibit miR-21 transcription. Furthermore, the inhibitor demonstrated cytotoxicity in a cervical cancer cell line via induction of apoptosis and was capable of reducing microtumor formation in a long-term clonogenic assay. Altogether, this work reports the discovery of a new small molecule inhibitor of miR-21 and demonstrates its potential as an alternative approach in cancer therapy.