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.

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.

Colorimetric PCR-Based microRNA Detection Method Based on Small Organic Dye and Single Enzyme.

microRNAs (miRNAs) have been a class of promising disease diagnostic biomarkers and therapeutic targets for their important biological functions. However, because of the high homology, interference from precursors (pri-miRNA, pre-miRNA), as well as limitations in the current assay technologies, it poses high demand and challenge for a specific, efficient, and economic miRNA assay method. Here, we propose a new miRNA detection method based on a label-free probe and a small organic dye with sequence dependence, realizing the sequence-specific and colorimetric detection of target miRNA. What is pleasantly surprising, only one enzyme is enough to propel the whole miRNA assay process, greatly simplifying the reaction component and detection process. Together with PCR amplification for the high enough sensitivity and three checks for specificity control, a detection limit of 5 fM was obtained and even one mutation could be discriminated visually. Overall, the new method makes much progress in convenience and economy of PCR-based miRNA assay method so that miRNA assay is going to be more friendly and affordable.

Plasiatine, an Unprecedented Indole-Phenylpropanoid Hybrid from Plantago asiatica as a Potent Activator of the Nonreceptor Protein Tyrosine Phosphatase Shp2.

Plasiatine (1), isolated from the seeds of Plantago asiatica, is an unprecedented indole analogue linked to a phenylpropanoid moiety via a carbon bond that builds up a novel heteromeric construction with a C19N2 scaffold. Its structure was determined by spectroscopic data and computational evidence. Notably, experimental assay demonstrated that 1 significantly enhanced the activity of the nonreceptor protein tyrosine phosphatase Shp2 in vitro in a concentration-dependent manner with an EC50 value of 0.97 µM, and activated phosphorylation of ERK, a known target of Shp2. Moreover, plasiatine (1) promoted hepatocellular HepG2 cells migration. Molecular docking suggested that plasiatine (1) binds to the catalytic cleft of Shp2. These results identified plasiatine (1) as the first small molecule Shp2 activator, and it warrants further investigation as a novel pharmaceutical tool to study the function of Shp2 in tumorigenesis.