Identification of a Novel TAR RNA-Binding Protein 2 Modulator with Potential Therapeutic Activity against Hepatocellular Carcinoma

Imbalance
miRNAs contribute to tumor formation; therefore, the
development of small-molecule compounds that regulate miRNA biogenesis
is an important strategy in oncotherapy. Here, (−)-Gomisin
M1 (GM) was found to modulate miRNA biogenesis to inhibit the proliferation,
migration, and invasion of hepatocellular carcinoma (HCC) cells. GM
modulated expression profiles of miRNA and protein in HCC cells and
suppressed tumor growth in a mouse model. Mechanistically, GM affected
miRNA maturation by targeting TAR RNA-binding protein 2 (TRBP), with
an efficacy higher than that of enoxacin, and promoted the binding
of TRBP with Dicer. Structural simplification and a preliminary structure–activity
relationship study via the synthesis of 20 GM derivatives showed that
compound 9 exhibited more potent inhibitory activity
in HCC cell proliferation and affinity for TRBP than did GM. These
results suggest that TRBP may be a novel potential therapeutic target
in HCC and compound 9 may be a potential drug candidate
for the treatment of HCC.