Discovery of a Novel Small-Molecule Inhibitor Disrupting TRBP–Dicer Interaction against Hepatocellular Carcinoma via the Modulation of microRNA Biogenesis

MicroRNAs
(miRNAs) are key players in human hepatocellular carcinoma
(HCC) tumorigenesis. Therefore, small molecules targeting components
of miRNA biogenesis may provide new therapeutic means for HCC treatment.
By a high-throughput screening and structural simplification, we identified
a small molecule, CIB-3b, which suppresses the growth and metastasis
of HCC in vitro and in vivo by modulating
expression profiles of miRNAome and proteome in HCC cells. Mechanistically,
CIB-3b physically binds to transactivation response (TAR) RNA-binding
protein 2 (TRBP) and disrupts the TRBP–Dicer interaction, thereby
altering the activity of Dicer and mature miRNA production. Structure–activity
relationship study via the synthesis of 45 CIB-3b derivatives showed
that some compounds exhibited a similar inhibitory effect on miRNA
biogenesis to CIB-3b. These results support TRBP as a potential therapeutic
target in HCC and warrant further development of CIB-3b along with
its analogues as a novel therapeutic strategy for the treatment of
HCC.