A 3,4-diamino-substituted coumarin derivative as a TRBP inhibitor suppresses tumor growth in breast cancer by inducing cellular senescence.

Transactivation response RNA-binding protein 2 (TRBP) mediates microRNA (miRNA) biogenesis and regulates messenger RNA (mRNA) stability. It is a pivotal regulator of post-transcriptional gene expression, influencing processes including cellular senescence and tumorigenesis. Elevated TRBP expression correlates with poor prognosis in breast cancer, underscoring its potential as a therapeutic target. We identified a 3,4-diamino-substituted coumarin derivative (3ai), a novel small-molecule compound inhibitor of miR-21 biogenesis. Compound 3ai increased the expression of tumor-suppressor proteins targeted by miR-21. Further mechanistic studies revealed that 3ai binds TRBP and disrupts the biogenesis of senescence-associated miRNAs. This interaction induces cell cycle arrest and DNA damage in tumor cells, ultimately promoting cellular senescence in breast cancer cells and suppressing their proliferation and metastasis potential. Our study reveals that 3ai directly engages TRBP to modulate miRNA biogenesis, thereby inducing cellular senescence. These results support TRBP as a therapeutic target in breast cancer and warrant further development of 3ai as a candidate therapeutic for breast cancer.