Exploring Small Molecule Drugs for MicroRNA Modulation: A Strategic Approach

MicroRNAs (miRNAs) regulate fundamental biological processes by silencing mRNA targets and are dysregulated in many diseases. However, modulating miRNAs through gene therapy or synthetic oligonucleotides has serious limitations, particularly poor delivery, resulting in delays and the absence of FDA-approved miRNA therapeutics. As an innovative alternative approach, we established the first high-throughput screen of the effects of 1370 small molecule compounds on neuronal miRNAnome. We demonstrate the utility of the screen by identifying cardiac glycosides as potent inducers of miR-132, a key neuroprotective miRNA downregulated in Alzheimer’s disease and other dementias. Coordinately, cardiac glycosides downregulate known miR-132 targets, including Tau, and protect rodent and human neurons against various toxic insults. Our ongoing work identifies a robust activator of miR-124, a driver of neuronal differentiation. A drug combination upregulating miR-124 and miR-132 arrests cell proliferation and promotes the differentiation of multiple neuroblastoma and glioblastoma cell models, suggesting new therapeutics for these cancers. More broadly, our dataset provides a valuable resource for discovering small molecule inhibitors or activators of miRNAs implicated in various diseases.