2. Academic Validation
  3. Discovery of a Novel Small-Molecule Inhibitor Disrupting TRBP-Dicer Interaction against Hepatocellular Carcinoma via the Modulation of microRNA Biogenesis

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

  • J Med Chem. 2022 Aug 25;65(16):11010-11033. doi: 10.1021/acs.jmedchem.2c00189.
Ting Peng 1 2 3,  Yujiao He 1 2,  Tao Wang 1,  Jialing Yu 1 3,  Xiaofang Ma 4,  Zongyuan Zhou 1 3,  Yuwen Sheng 1 3,  Lingyu Li 1 3,  Huipan Peng 1,  Sheng Li 1,  Jiawei Zou 1,  Yi Yuan 1,  Yongyun Zhao 1,  Hailong Shi 1 3,  Fu Li 1,  Wanli Liu 5,  Kaifeng Hu 4,  Xiaoxia Lu 1,  Guolin Zhang 1 6,  Fei Wang 1 6
Affiliations

Affiliations

  • 1 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
  • 2 Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
  • 5 Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China.
  • 6 Xiongan Institute of Innovation, Chinese Academy of Sciences, Hebei 071700, China.
PMID: 35695407 DOI: 10.1021/acs.jmedchem.2c00189
Abstract

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.

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