更新于：2024-11-01

NSD2 x HDAC2

更新于：2024-11-01

基本信息

关联

项与 NSD2 x HDAC2 相关的药物

DT-NH-1

靶点

HDAC2 x NSD2

作用机制

HDAC2抑制剂 [+1]

在研机构

扬州大学

原研机构

扬州大学

在研适应症

肝癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 NSD2 x HDAC2 相关的临床结果

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100 项与 NSD2 x HDAC2 相关的转化医学

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0 项与 NSD2 x HDAC2 相关的专利（医药）

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项与 NSD2 x HDAC2 相关的文献（医药）

2024-12-31·Journal of Enzyme Inhibition and Medicinal Chemistry

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

Article

作者: Jin, Xing ; Niu, Miaomiao ; Yang, Yang ; Bao, Guangyu ; Wang, Yuting ; Chen, Jing ; Zhang, Qiaoxuan

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.

2008-03-15·Blood1区 · 医学

The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor

1区 · 医学

Article

作者: Shimoyama, Manabu ; Walsh, Martin J. ; Bergsagel, P. Leif ; Zhou, Ming-Ming ; Marango, Jotin ; Waxman, Samuel ; Nishio, Hitomi ; Min, Dong-Joon ; Licht, Jonathan D. ; Martinez-Martinez, Yolanda ; Meyer, Julia A. ; Chesi, Marta ; Leibovitch, Boris A. ; Sirulnik, Andres

AbstractMMSET, identified by its fusion to the IgH locus in t(4;14)-associated multiple myeloma, possesses domains found within chromatin regulators, including the SET domain. MMSET protein is overexpressed and highly associated with chromatin in myeloma cell lines carrying t(4;14). MMSET possesses methyltransferase activity for core histone H3 lysine 4 and histone 4 lysine 20, whereas MMSET made in cells only modified H4. Segments of MMSET fused to the Gal4 DNA binding domain repressed transcription of a chromatin-embedded Gal4 reporter gene. MMSET-mediated repression was associated with increased H4K20 methylation gene and loss of histone acetylation. Consistent with this repressive activity, MMSET could form a complex with HDAC1 and HDAC2, mSin3a, and the histone demethylase LSD1, suggesting that it is a component of corepressor complexes. Furthermore, MMSET coexpression enhances HDAC1- and HDAC2-mediated repression in transcriptional reporter assays. Finally, shRNA-mediated knockdown of MMSET compromised viability of a myeloma cell line, suggesting a biologic role for the protein in malignant cell growth. Collectively, these data suggest that, by acting directly as a modifier of chromatin as well as through binding of other chromatin-modifying enzymes, MMSET influences gene expression and potentially acts as a pathogenic agent in multiple myeloma.

2005-10-01·British Journal of Haematology2区 · 医学

Transcription repression activity is associated with the type I isoform of the MMSET gene involved in t(4;14) in multiple myeloma

2区 · 医学

Article

作者: Alberto Zanella ; Domenica Ronchetti ; Katia Todoerti ; Stefano Castellani ; Luigia Lombardi ; Giorgio Lambertenghi Deliliers ; Luca Agnelli ; Antonino Neri ; Silvia Marelli

SummaryThe WHSC1/MMSET gene, involved in t(4;14)(p16.3;q32) in multiple myeloma, encodes putative isoforms (MMSET I, MMSET II and RE‐IIBP) which are thought to be involved in transcription regulation. We investigated their activity in transfected 293T and HeLa cells. Both MMSET I and MMSET II were localised in the nucleus, whereas RE‐IIBP showed cytoplasmic and nucleolar staining. MMSET I dose‐dependently repressed the transcriptional activity of the promoter region of the thymidine kinase gene, whereas MMSET II and RE‐IIBP had no effect. The HDAC inhibitor, trichostatin A, reduced MMSET I repression activity and in vitro co‐immunoprecipitation analyses indicated that MMSET I specifically recruits HDAC1 and mSin3b, but not HDAC2 or HDAC4. Our data support the hypothesis that MMSET may act as a transcription regulator; different functions may be associated with distinct isoforms.