Peng Ting, He Yujiao, Wang Tao, Yu Jialing, Ma Xiaofang, Zhou Zongyuan, Sheng Yuwen, Li Lingyu, Peng Huipan, Li Sheng, Zou Jiawei, Yuan Yi, Zhao Yongyun, Shi Hailong, Li Fu, Liu Wanli, Hu Kaifeng, Lu Xiaoxia, Zhang Guolin, Wang Fei
Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China.
J Med Chem. 2022 Aug 25;65(16):11010-11033. doi: 10.1021/acs.jmedchem.2c00189. Epub 2022 Jun 13.
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 and 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.
微小RNA（miRNA）是人类肝细胞癌（HCC）肿瘤发生的关键因素。因此，靶向miRNA生物合成成分的小分子可能为HCC治疗提供新的治疗手段。通过高通量筛选和结构简化，我们鉴定出一种小分子CIB-3b，它通过调节HCC细胞中miRNA组和蛋白质组的表达谱来抑制HCC的生长和转移。从机制上讲，CIB-3b与反式激活应答（TAR）RNA结合蛋白2（TRBP）发生物理结合，并破坏TRBP-核酸酶Dicer的相互作用，从而改变Dicer的活性和成熟miRNA的产生。通过合成45种CIB-3b衍生物进行的构效关系研究表明，一些化合物对miRNA生物合成表现出与CIB-3b相似的抑制作用。这些结果支持TRBP作为HCC的潜在治疗靶点，并证明有必要进一步开发CIB-3b及其类似物，作为治疗HCC的一种新型治疗策略。
