Reversing the Hypoxic Adaptive Response in Breast Cancer Cells through Small-Molecule Inhibition of Oncogenic MicroRNA-210.

MicroRNA-210 (miR-210) is a key regulator of the hypoxic adaptive response in cancer cells, making it an attractive therapeutic target. In our continuous search for small-molecule inhibitors of oncogenic miRNAs, we designed a novel series of tris-thiazole-based compounds to interfere with miR-210 biogenesis. Through structural optimization, we identified new pre-miR-210 ligands, which exhibited a submicromolar affinity for the miR-210 precursor and potently inhibited its maturation in vitro. In breast cancer cells exposed to hypoxic conditions, the most active compound effectively reversed the hypoxic adaptive response, leading to reduced expression of hypoxia-inducible factors and their downstream targets. These findings demonstrate the potential of the tris-thiazole scaffold as a chemical probe and an RNA binder while highlighting the therapeutic relevance of miR-210 inhibition in hypoxia-driven cancers. Indeed, the inhibition of miR-210 biogenesis by small molecules reverses the hypoxia-induced adaptive phenotype in cancer cells.