更新于：2024-11-01

c-Myc x GNMT

更新于：2024-11-01

基本信息

关联

项与 c-Myc x GNMT 相关的药物

K117

靶点

GNMT x c-Myc

作用机制

GNMT agonists [+1]

在研机构

辅仁大学

原研机构

辅仁大学

在研适应症

肝细胞癌

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 c-Myc x GNMT 相关的临床结果

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100 项与 c-Myc x GNMT 相关的转化医学

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0 项与 c-Myc x GNMT 相关的专利（医药）

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项与 c-Myc x GNMT 相关的文献（医药）

2021-07-08·Journal of Medicinal Chemistry1区 · 医学

Discovery of an Orally Efficacious MYC Inhibitor for Liver Cancer Using a GNMT-Based High-Throughput Screening System and Structure–Activity Relationship Analysis

1区 · 医学

Article

作者: Yang, Ming-Hui ; Chen, Yeh-Long ; Chen, Yi-Ming Arthur ; Chen, Marcelo ; Tseng, Chih-Hua ; Tzeng, Cherng-Chyi ; Tyan, Yu-Chang ; Kant, Rajni ; Chen, Wei-Cheng ; You, Kaiting ; Li, Wei-You ; Wang, Wen-Chieh ; Yen, Chia-Hung

Glycine-N-methyl transferase (GNMT) downregulation results in spontaneous hepatocellular carcinoma (HCC). Overexpression of GNMT inhibits the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is a potential approach for anti-HCC therapy. Herein, we used Huh7 GNMT promoter-driven screening to identify a GNMT inducer. Compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure-activity relationship analysis and found a potent GNMT inducer, K117. K117 inhibited Huh7 cell growth in vitro and xenograft in vivo. Oral administration of a dosage of K117 at 10 mpk (milligrams per kilogram) can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib at a dosage of 25 mpk. A mechanistic study revealed that K117 is an MYC inhibitor. Ectopic expression of MYC using CMV promoter blocked K117-mediated MYC inhibition and GNMT induction. Overall, K117 is a potential lead compound for HCC- and MYC-dependent cancers.

2019-02-14·Clinical Science2区 · 医学

Hepatic accumulation of S-adenosylmethionine in hamsters with non-alcoholic fatty liver disease associated with metabolic syndrome under selenium and vitamin E deficiency

2区 · 医学

Article

作者: Maria del Bas, Josep ; Arola, Lluís ; Rodríguez, Benjamín ; Mariné, Silvia ; Armengol, Lluís ; Rodríguez, Miguel Angel ; Caimari, Antoni ; Moriña, David ; Puiggròs, Francesc

AbstractProgression of non-alcoholic fatty liver disease (NAFLD) in the context of metabolic syndrome (MetS) is only partially explored due to the lack of preclinical models. In order to study the alterations in hepatic metabolism that accompany this condition, we developed a model of MetS accompanied by the onset of steatohepatitis (NASH) by challenging golden hamsters with a high-fat diet low in vitamin E and selenium (HFD), since combined deficiency results in hepatic necroinflammation in rodents. Metabolomics and transcriptomics integrated analyses of livers revealed an unexpected accumulation of hepatic S-Adenosylmethionine (SAM) when compared with healthy livers likely due to diminished methylation reactions and repression of GNMT. SAM plays a key role in the maintenance of cellular homeostasis and cell cycle control. In agreement, analysis of over-represented transcription factors revealed a central role of c-myc and c-Jun pathways accompanied by negative correlations between SAM concentration, MYC expression and AMPK phosphorylation. These findings point to a drift of cell cycle control toward senescence in livers of HFD animals, which could explain the onset of NASH in this model. In contrast, hamsters with NAFLD induced by a conventional high-fat diet did not show SAM accumulation, suggesting a key role of selenium and vitamin E in SAM homeostasis. In conclusion, our results suggest that progression of NAFLD in the context of MetS can take place even in a situation of hepatic SAM excess and that selenium and vitamin E status might be considered in current therapies against NASH based on SAM supplementation.

2012-06-01·Cellular Oncology2区 · 医学

An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis

2区 · 医学

ArticleOA

作者: Maria L. Tomasi ; Francesco Feo ; Maria M. Simile ; Rosa M. Pascale ; Lucia Daino ; Giuliana Solinas ; Maria I. Demartis ; Stefania Brozzetti ; Claudio F. Feo ; Ju Seog Lee ; Giovanni Massarelli ; Maddalena Frau ; Maria A. Seddaiu

BACKGROUND AND AIMSHepatocarcinogenesis is under polygenic control. We analyzed gene expression patterns of dysplastic liver nodules (DNs) and hepatocellular carcinomas (HCCs) chemically-induced in F344 and BN rats, respectively susceptible and resistant to hepatocarcinogenesis.METHODSExpression profiles were performed by microarray and validated by quantitative RT-PCR and Western blot.RESULTSCluster analysis revealed two distinctive gene expression patterns, the first of which included normal liver of both strains and BN nodules, and the second one F344 nodules and HCC of both strains. We identified a signature predicting DN and HCC progression, characterized by highest expression of oncosuppressors Csmd1, Dmbt1, Dusp1, and Gnmt, in DNs, and Bhmt, Dmbt1, Dusp1, Gadd45g, Gnmt, Napsa, Pp2ca, and Ptpn13 in HCCs of resistant rats. Integrated gene expression data revealed highest expression of proliferation-related CTGF, c-MYC, and PCNA, and lowest expression of BHMT, DMBT1, DUSP1, GADD45g, and GNMT, in more aggressive rat and human HCC. BHMT, DUSP1, and GADD45g expression predicted patients' survival.CONCLUSIONSOur results disclose, for the first time, a major role of oncosuppressor genes as effectors of genetic resistance to hepatocarcinogenesis. Comparative functional genomic analysis allowed discovering an evolutionarily conserved gene expression signature discriminating HCC with different propensity to progression in rat and human.