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

Zongyuan Zhou; Yiming Li; Xiaofang Ma; Biyun Cao; Ting Peng; Yuwen Sheng; Huipan Peng; Runze Li; Yu Cao; Ruiying Xi; Fu Li; Mengru Wang; Handong Sun; Guolin Zhang; Hongbin Zhang; Kaifeng Hu; Weilie Xiao; Fei Wang

doi:10.1021/acs.jmedchem.1c00018

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

J Med Chem. 2021 Jun 10;64(11):7404-7421. doi: 10.1021/acs.jmedchem.1c00018. Epub 2021 May 26.

Authors

Zongyuan Zhou^{1

2}, Yiming Li³, Xiaofang Ma⁴, Biyun Cao³, Ting Peng^{1

2}, Yuwen Sheng^{1

2}, Huipan Peng^{1

2}, Runze Li^{1

2}, Yu Cao^{1

2}, Ruiying Xi^{1

2}, Fu Li¹, Mengru Wang³, Handong Sun⁵, Guolin Zhang¹, Hongbin Zhang³, Kaifeng Hu⁴, Weilie Xiao³, Fei Wang^{1

6}

Affiliations

¹ Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China.
⁴ Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
⁵ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
⁶ Xiongan Institute of Innovation, Chinese Academy of Sciences, Hebei 071700, China.

PMID: 34038111
DOI: 10.1021/acs.jmedchem.1c00018

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular / drug therapy
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / pathology
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
DEAD-box RNA Helicases / chemistry
DEAD-box RNA Helicases / metabolism
Enoxacin / chemistry
Enoxacin / metabolism
Enoxacin / pharmacology
Enoxacin / therapeutic use
Gene Expression Regulation, Neoplastic / drug effects
Humans
Liver Neoplasms / drug therapy
Liver Neoplasms / genetics
Liver Neoplasms / pathology
Mice
Mice, Nude
MicroRNAs / metabolism
Polycyclic Compounds / chemistry*
Polycyclic Compounds / metabolism
Polycyclic Compounds / pharmacology
Polycyclic Compounds / therapeutic use
Proteome / drug effects
Proteome / metabolism
RNA-Binding Proteins / antagonists & inhibitors
RNA-Binding Proteins / metabolism*
Ribonuclease III / chemistry
Ribonuclease III / metabolism
Structure-Activity Relationship
Transcriptome / drug effects
Transplantation, Heterologous

Substances

MicroRNAs
Polycyclic Compounds
Proteome
RNA-Binding Proteins
trans-activation responsive RNA-binding protein
Enoxacin
DICER1 protein, human
Ribonuclease III
DEAD-box RNA Helicases