Novel dual-targeting inhibitors of NSD2 and HDAC2 for the treatment of liver cancer: structure-based virtual screening, molecular dynamics simulation, and in vitro and in vivo biological activity evaluations

Abstract

Liver cancer exhibits a high degree of heterogeneity and involves intricate mechanisms. Recent research has revealed the significant role of histone lysine methylation and acetylation in the epigenetic regulation of liver cancer development. In this study, five inhibitors capable of targeting both histone lysine methyltransferase nuclear receptor-binding SET domain 2 (NSD2) and histone deacetylase 2 (HDAC2) were identified using a structure-based virtual screening approach. Notably, DT-NH-1 displayed a potent inhibition of NSD2 (IC₅₀ = 0.08 ± 0.03 μM) and HDAC2 (IC₅₀ = 5.24 ± 0.87 nM). DT-NH-1 also demonstrated a strong anti-proliferative activity against various liver cancer cell lines, particularly HepG2 cells, and exhibited a high level of biological safety. In an experimental xenograft model involving HepG2 cells, DT-NH-1 showed a significant reduction in tumour growth. Consequently, these findings indicate that DT-NH-1 will be a promising lead compound for the treatment of liver cancer with epigenetic dual-target inhibitors.

Keywords:

• Liver cancer
• NSD2
• HDAC2
• dual-targeting inhibitors
• virtual screening

Ethical statement

All experimental protocols were reviewed and approved by the Animal Ethics Committee of China Pharmaceutical University.

Author contributions

GB, QZ and XJ contributed to the conception of the study. YW, XJ and MMN performed experiments and acquired data. YW, JC, MMN, and YY performed statistical analysis. XJ and YW contributed significantly to manuscript preparation. All authors had contributed and approved the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was financially supported by Guangzhou Science and Technology Plan Projects [2023A03J0755]; “Young Talents Program” of Guangdong Academy of Traditional Chinese Medicine [SZ2022QN09].