更新于：2024-11-01

NFAT1 x MDM2

更新于：2024-11-01

基本信息

关联

项与 NFAT1 x MDM2 相关的药物

MA242

靶点

MDM2 x NFAT1

作用机制

MDM2抑制剂 [+1]

在研机构

University of Houston

原研机构

University of Houston

在研适应症

乳腺癌

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 NFAT1 x MDM2 相关的临床结果

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100 项与 NFAT1 x MDM2 相关的转化医学

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0 项与 NFAT1 x MDM2 相关的专利（医药）

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项与 NFAT1 x MDM2 相关的文献（医药）

2023-08-15·The EMBO Journal

LncRNA NRON promotes tumorigenesis by enhancing MDM2 activity toward tumor suppressor substrates

Article

作者: Zhang, Yunmei ; Song, Erwei ; Li, Yihui ; Shen, Liping ; Lin, Huayue ; Luo, Man-Li ; Guo, Qiannan ; Chen, Jianing

AbstractThe E3 ligase MDM2 promotes tumor growth and progression by inducing ubiquitin‐mediated degradation of P53 and other tumor‐suppressing proteins. Here, we identified an MDM2‐interacting lncRNA NRON, which promotes tumor formation by suppressing both P53‐dependent and independent pathways. NRON binds to MDM2 and MDMX (MDM4) via two different stem‐loops, respectively, and induces their heterogenous dimerization, thereby enhancing the E3 ligase activity of MDM2 toward its tumor‐suppressing substrates, including P53, RB1, and NFAT1. NRON knockdown dramatically inhibits tumor cell growth in vitro and in vivo. More importantly, NRON overexpression promotes oncogenic transformation by inducing anchorage‐independent growth in vitro and facilitating tumor formation in immunocompromised mice. Clinically, NRON expression is significantly associated with poor clinical outcome in breast cancer patients. Together, our data uncover a pivotal role of lncRNA that induces malignant transformation of epithelial cells by inhibiting multiple tumor suppressor proteins.

2022-03-01·Inflammation Research3区 · 医学

Japonicone A and related dimeric sesquiterpene lactones: molecular targets and mechanisms of anticancer activity

3区 · 医学

Review

作者: Vergoten, Gérard ; Bailly, Christian

OBJECTIVE AND DESIGNJaponicone A (Jap-A) is a sesquiterpene lactone (SL) dimer isolated from the plant Inula japonica Thunb. and the leading compound in the japonicone series of SL dimers which comprises 25 members (Jap-A to Jap-Y). We have analyzed the anticancer properties of Jap-A and the associated molecular targets.METHODSAll literature data on japonicones and related SL dimers, including inulanolide A (Inu-A) and lineariifolianoid A (Lin-A) have been analyzed. Molecular models of the compound/target interactions were constructed to support our analysis.RESULTSInulae Flos (Xuan Fu Hua) is used in traditional medicine in China and Korea to treat inflammatory diseases. The plant contains diverse japonicones and structurally related SL dimers. The interactions of Jap-A with the two main proteins, the pro-inflammatory cytokine TNF-α and the ubiquitin ligase MDM2, are at the origin of the anti-inflammatory and anticancer effects. Molecular docking analyses suggest that Inu-A is better adapted than Lin-A and Jap-A to form stable complexes with both TNF-α and MDM2. Jap-A exhibits marked capacities to inhibit cancer cell proliferation and dissemination and to trigger apoptosis, both in vitro and in vivo in several tumor models in mice. Its analogue Inu-A is more potent, functioning as a dual inhibitor of the MDM2-NFAT1 pathway.CONCLUSIONThis review shed some new light on the molecular targets and potential therapeutic benefits of these SL dimers and should help the design of novel anticancer agents derived from these compounds.

2019-09-01·Cancer Letters1区 · 医学

MDM2-NFAT1 dual inhibitor, MA242: Effective against hepatocellular carcinoma, independent of p53

1区 · 医学

Article

作者: Nijampatnam, Bhavitavya ; Zhang, Ruiwen ; Wang, Wei ; Hu, Bo ; Li, Xin ; Fan, Jia ; Cheng, Jian-Wen ; Yang, Xin-Rong ; Qin, Jiang-Jiang ; Velu, Sadanandan E

The overexpression of the MDM2 oncoprotein frequently occurs in hepatocellular carcinoma (HCC). Small molecules that inhibit MDM2-p53 binding show efficacy against p53 wild-type HCC, but most patients have p53-mutant tumors and intrinsic resistance to such MDM2 inhibitors. We have recently discovered that the NFAT1 transcription factor upregulates MDM2 expression, but the role of NFAT1 in HCC is not fully understood. The present study was designed to develop a dual-targeting (MDM2 and NFAT1) strategy for the treatment of HCC. We herein demonstrate that high expression levels of NFAT1 and MDM2 are independent predictors of a poor prognosis in patients with HCC. We have also identified a MDM2 and NFAT1 dual inhibitor (termed MA242) that induces MDM2 auto-ubiquitination and degradation and represses NFAT1-mediated MDM2 transcription. MA242 profoundly inhibits the growth and metastasis of HCC cells in vitro and in vivo, independent of p53. The present efficacy and mechanistic studies provide proof-of-principle data to support the therapeutic value of this dual targeting strategy in future drug discovery.