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Abnormal function of RNA-binding proteins can lead to dysregulation of RNA function, causing a variety of disease states. Thus, developing small-molecule modulators of protein-RNA interactions is one of the key challenges in chemical biology. Herein, we performed a high-throughput screening of chemical libraries using a Förster resonance energy transfer-based Lin28-let-7 interaction assay to identify a potent small-molecule inhibitor of the protein-microRNA interaction, as it is an important target implicated in stem cell-like phenotypes in cancer cells. The new inhibitor KCB3602 selectively restored cellular let-7 microRNA levels, decreased the expression of a panel of oncogenes responsible for cancer stem cell maintenance, and showed potential anticancer activities. We expect that our Lin28-let-7 interaction inhibitor will provide a good starting point for pharmacological eradication of cancer stem cells.

Restoring Let-7 microRNA Biogenesis Using a Small-Molecule Inhibitor of the Protein–RNA Interaction