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
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 h...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2289355 |
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| author | Xing Jin Yuting Wang Jing Chen Miaomiao Niu Yang Yang Qiaoxuan Zhang Guangyu Bao |
| author_facet | Xing Jin Yuting Wang Jing Chen Miaomiao Niu Yang Yang Qiaoxuan Zhang Guangyu Bao |
| author_sort | Xing Jin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-22b604f5c6384211ba65b8aee18b01df |
| institution | Kabale University |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-22b604f5c6384211ba65b8aee18b01df2024-12-26T09:30:44ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2023.2289355Novel 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 evaluationsXing Jin0Yuting Wang1Jing Chen2Miaomiao Niu3Yang Yang4Qiaoxuan Zhang5Guangyu Bao6Department of Laboratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, ChinaDepartment of Laboratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, ChinaDepartment of Laboratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, ChinaDepartment of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, ChinaDepartment of Laboratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, ChinaLiver 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.https://www.tandfonline.com/doi/10.1080/14756366.2023.2289355Liver cancerNSD2HDAC2dual-targeting inhibitorsvirtual screening |
| spellingShingle | Xing Jin Yuting Wang Jing Chen Miaomiao Niu Yang Yang Qiaoxuan Zhang Guangyu Bao 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 Journal of Enzyme Inhibition and Medicinal Chemistry Liver cancer NSD2 HDAC2 dual-targeting inhibitors virtual screening |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Liver cancer NSD2 HDAC2 dual-targeting inhibitors virtual screening |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2289355 |
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