Functional microRNA-targeting drug discovery by graph-based deep learning.

MicroRNAs are recognized as key drivers in many cancers but targeting them with small molecules remains a challenge. We present RiboStrike, a deep-learning framework that identifies small molecules against specific microRNAs. To demonstrate its capabilities, we applied it to microRNA-21 (miR-21), a known driver of breast cancer. To ensure selectivity toward miR-21, we performed counter-screens against miR-122 and DICER. Auxiliary models were used to evaluate toxicity and rank the candidates. Learning from various datasets, we screened a pool of nine million molecules and identified eight, three of which showed anti-miR-21 activity in both reporter assays and RNA sequencing experiments. Target selectivity of these compounds was assessed using microRNA profiling and RNA sequencing analysis. The top candidate was tested in a xenograft mouse model of breast cancer metastasis, demonstrating a significant reduction in lung metastases. These results demonstrate RiboStrike's ability to nominate compounds that target the activity of miRNAs in cancer.