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 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.