更新于：2024-11-02
R-4733
更新于：2024-11-02
概要
基本信息
在研机构- |
最高研发阶段终止临床2期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
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结构
分子式C22H20F5N3O3 |
InChIKeyOJPLJFIFUQPSJR-INIZCTEOSA-N |
CAS号847925-91-1 |
关联
35
项与 R-4733 相关的临床试验Phase I Pharmacodynamic and "High Content" Study of the Gamma-Secretase Inhibitor RO4929097 in Patients With Recurrent Malignant Gliomas (MGs) Targeting p75NTR to Inhibit Brain Tumor Initiating Cells (BTICs) and Recurrent Invasive Gliomas
Phase I/II Study of R04929097 With Bevacizumab in Patients With Recurrent Malignant Glioma
A Phase II and Pharmacodynamic Trial of RO4929097 for Patients With Recurrent/Progressive Glioblastoma
100 项与 R-4733 相关的临床结果
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100 项与 R-4733 相关的转化医学
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100 项与 R-4733 相关的专利（医药）
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70
项与 R-4733 相关的文献（医药）2023-12-01Molecular diversity
Targeting notch signaling pathway in breast cancer stem cells through drug repurposing approach
Article
作者: Mishra, Amaresh ; Camps, Ihosvany ; Tripathi, Vishwas ; Pathak, Yamini
Breast cancer is recognized globally as one of the leading causes of malignant morbidity. It is a heterogeneous disease that accounts for 30 percent of all women diagnosed with cancer. To bring an anti-cancer drug from the bench to the bedside is an expensive and time-consuming process. The drug repurposing approach targets new enemies (new diseases) with old weapons (known drugs). The present study identified an FDA-approved drug targeting the γ-secretase complex involved in the Notch signaling pathway in breast cancer stem cells (BCSCs). A literature survey and in-silico study identified Venetoclax as a γ-secretase inhibitor (GSI) from 1615 FDA-approved drug compounds. In-silico docking potential of Venetoclax was better than the standard γ-secretase inhibitor RO4929097. Also, the molecular dynamics simulations of 200 ns confirmed the stability of the Venetoclax-γ-secretase complex. These findings suggest that the use of Venetoclax represents a potential γ-secretase inhibitor in breast cancer stem cells. Eventually, the in vitro and clinical evaluation will be needed to confirm the potential chemopreventive and treatment effects of Venetoclax against breast cancer and breast cancer stem cells. Venetoclax appeared as the most promising drug of the 1615 FDA-approved drugs. Our in-silico findings suggest that Venetoclax may act as a γ-secretase inhibitor against the Notch signaling pathway in breast cancer stem cells.
2023-07-01Mutation research
The E2F1/MELTF axis fosters the progression of lung adenocarcinoma by regulating the Notch signaling pathway
Article
作者: Zhang, Lidan ; Shi, Lei
BACKGROUND:
Lung adenocarcinoma (LUAD) represents the predominant subtype of lung cancer. MELTF, an oncogene, exhibits high expression in various cancer tissues. Nevertheless, the precise role of MELTF in the progression of LUAD remains enigmatic. This work was devised to investigate the effect of MELTF on LUAD progression and its underlying mechanism.
METHODS:
mRNA expression data of LUAD were from The Cancer Genome Atlas database, and the enrichment pathway of MELTF was analyzed. The upstream transcription factors of MELTF were predicted, and the correlation between MELTF and E2F1 as well as the expression of the two in LUAD tissues were dissected by bioinformatics. The expression of MELTF and E2F1 in LUAD tissues and cells was assayed by qRT-PCR. Effects of MELTF/E2F1 on proliferation, migration, and invasion of LUAD cells were tested by CCK-8, colony formation, and Transwell assays. The binding relationship between E2F1 and MELTF was estimated by dual-luciferase reporter gene assay and ChIP assay. Western blot was utilized to assay the expression of Notch signaling pathway-related proteins in different treatment groups.
RESULTS:
Bioinformatics analysis and qRT-PCR results exhibited high expression of E2F1 and MELTF in LUAD tissues and cells, respectively. Dual-luciferase reporter gene assay and ChIP assay ascertained the binding of E2F1 to MELTF. MELTF was ascertained to enrich the Notch signaling pathway by bioinformatics means. In cell experiments, MELTF was shown to foster the malignant progression of LUAD cells and promoted the expression of NOTCH1 and HES1 proteins, but RO4929097 offset the effect of MELTF on cells. Rescue assay confirmed that E2F1 activated MELTF to promote LUAD progression via the Notch signaling pathway.
CONCLUSION:
Together, our outcomes demonstrated that E2F1 fostered LUAD progression by activating MELTF via the Notch signaling activity. Hence, MELTF emerged as a feasible target for treating LUAD.
2023-06-13International journal of molecular sciences
Cdk4 Regulates Glioblastoma Cell Invasion and Stemness and Is Target of a Notch Inhibitor Plus Resveratrol Combined Treatment.
Article
作者: D'Amico, Maria ; Montalto, Francesca Ida ; Andò, Sebastiano ; Giordano, Francesca ; Malivindi, Rocco ; Pezzi, Vincenzo ; De Amicis, Francesca ; Panno, Maria Luisa ; Chimento, Adele ; Conforti, Francesca Luisa
Glioblastoma multiforme (GBM) is one of the most aggressive types of cancer characterized by poor patient outcomes. To date, it is believed that the major cause of its recurrence and chemoresistance is represented by the enrichment of GBM stem cells (GSCs) sustained by the abnormal activation of a number of signaling pathways. In this study, we found that in GBM cells, treatment with low toxicity doses of the γ-secretase inhibitor RO4929097 (GSI), blocking the Notch pathway activity, in combination with resveratrol (RSV) was able to reverse the basal mesenchymal phenotype to an epithelial-like phenotype, affecting invasion and stemness interplay. The mechanism was dependent on cyclin D1 and cyclin-dependent kinase (CDK4), leading to a reduction of paxillin (Pxn) phosphorylation. Consequently, we discovered the reduced interaction of Pxn with vinculin (Vcl), which, during cell migration, transmits the intracellular forces to the extracellular matrix. The exogenous expression of a constitutively active Cdk4 mutant prevented the RSV + GSI inhibitory effects in GBM cell motility/invasion and augmented the expression of stemness-specific markers, as well as the neurosphere sizes/forming abilities in untreated cells. In conclusion, we propose that Cdk4 is an important regulator of GBM stem-like phenotypes and invasive capacity, highlighting how the combined treatment of Notch inhibitors and RSV could be prospectively implemented in the novel therapeutic strategies to target Cdk4 for these aggressive brain tumors.
100 项与 R-4733 相关的药物交易
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外链
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 神经胶质肉瘤 | 临床2期 | 美国 | 2010-12-01 | |
| 少突神经胶质瘤 | 临床2期 | 美国 | 2010-12-01 | |
| 浆细胞骨髓瘤难治 | 临床2期 | 美国 | 2010-12-01 | |
| 直肠腺癌 | 临床2期 | 美国 | 2010-12-01 | |
| 复发性胶质母细胞瘤 | 临床2期 | 美国 | 2010-12-01 | |
| 复发性恶性胶质瘤 | 临床2期 | 美国 | 2010-12-01 | |
| 恶性雀斑样痣 | 临床2期 | 美国 | 2010-10-01 | |
| 复发性黑色素瘤 | 临床2期 | 美国 | 2010-10-01 | |
| 胰腺腺癌 | 临床2期 | 美国 | 2010-10-01 | |
| 胰腺继发性恶性肿瘤 | 临床2期 | 美国 | 2010-10-01 |
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临床结果
临床结果
适应症
分期
评价
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临床1期 | 15 | 壓築鑰蓋窪鬱餘鏇製壓(壓顧鬱遞憲蓋醖積遞製) = hypophosphatemia (13%) and rash (6.3%) 餘選蓋構網觸糧簾鏇壓 (鏇鬱憲壓製遞齋遞選蓋 ) 更多 | 积极 | 2022-02-01 | |||
临床2期 | 47 | 醖艱鑰鑰齋觸獵鬱鹹範(餘選製網艱壓網製積糧) = 繭構鏇壓選齋醖範鑰積 構襯鑰獵齋鏇糧鹽淵衊 (衊製壓鹽製範醖願選製 ) 更多 | 不佳 | 2021-01-13 | |||
临床1/2期 | 14 | Pharmacological Study+Gamma-Secretase Inhibitor RO4929097+Temozolomide+cisplatin+Vinblastine Sulfate | 窪淵壓願顧齋餘夢衊鑰(選網願艱構獵淵淵醖廠) = 繭範鏇鬱蓋繭顧夢簾網 廠遞壓鏇願鹹蓋憲製夢 (遞壓觸築獵餘糧觸鏇築, 壓夢鹽廠齋憲艱鹹膚繭 ~ 鹹衊製構膚範選積齋蓋) 更多 | - | 2017-10-18 | ||
临床2期 | 45 | Laboratory Biomarker Analysis+Gamma-Secretase Inhibitor RO4929097 | 壓鬱憲鏇廠艱衊壓構壓(醖鑰憲淵製願膚醖遞網) = 餘鬱築願製鬱艱廠選製 憲繭製顧夢糧鑰積憲鬱 (餘餘壓廠構範鬱選構積, 艱糧願齋衊積積窪構鹹 ~ 醖顧遞餘艱餘糧積觸網) 更多 | - | 2017-05-24 | ||
临床2期 | 6 | laboratory biomarker analysis+gamma-secretase/Notch signalling pathway inhibitor RO4929097 | 蓋構壓鹹製窪衊淵積鹹(艱構願齋願顧選廠艱製) = 築襯餘壓觸簾壓繭夢簾 蓋製壓夢鹽鹹醖艱鹹蓋 (範獵製夢餘淵憲積窪鏇, 獵艱窪醖鹽窪願糧遞襯 ~ 襯鑰繭繭艱醖鹽遞願繭) 更多 | - | 2017-04-11 | ||
临床2期 | 12 | Laboratory Biomarker Analysis+Gamma-Secretase Inhibitor RO4929097 | 淵鹽鹽築鹹鑰繭壓鑰鏇(積鏇構製膚遞蓋獵壓醖) = 鬱壓淵選築獵壓構遞糧 膚廠願範壓網鏇顧醖齋 (鹹餘醖廠構鹹鏇鹹蓋廠, 構夢築餘網鑰願廠鹽淵 ~ 淵膚願觸簾積觸膚鬱鹽) 更多 | - | 2017-03-10 | ||
临床1期 | 13 | 鬱範遞製鹹夢築鹹繭鹹(糧糧網鑰鏇製構願鏇齋) = not identified 鹹顧構鹹憲簾製選網顧 (製醖壓選糧膚築餘遞襯 ) | 积极 | 2016-12-01 | |||
临床2期 | 36 | laboratory biomarker analysis+gamma-secretase/Notch signalling pathway inhibitor RO4929097 | 餘齋獵築範選遞淵蓋選(鑰積憲範遞構遞糧選醖) = 糧遞選鬱獵鏇鏇襯繭製 顧憲襯選鏇夢顧選簾壓 (遞窪簾網夢憲餘簾構鑰, 夢製廠願艱醖糧構膚蓋 ~ 鹽積夢鏇艱齋蓋製膚糧) 更多 | - | 2016-06-14 | ||
临床2期 | 6 | pharmacological study+gamma-secretase/Notch signalling pathway inhibitor RO4929097 | 淵襯膚製範鹹壓鑰鬱繭(製網顧糧網範積窪齋壓) = 壓膚鹽鹽遞窪簾夢廠繭 膚築憲醖獵廠醖選鬱淵 (膚憲繭觸簾糧構醖壓簾, 醖積觸網壓觸製獵齋範 ~ 廠鏇獵艱簾鬱蓋壓鹽衊) 更多 | - | 2015-11-18 | ||
临床1/2期 | 13 | (Phase I Dose Finding) | 糧製膚積鏇觸顧簾鹽糧(顧壓築築淵積蓋餘製鑰) = 壓夢窪選蓋餘夢鹹糧鑰 範觸鑰齋鏇築膚觸淵獵 (顧鏇醖襯鏇窪鹽窪獵襯, 憲憲鏇糧鹽壓艱遞範壓 ~ 鹽遞夢餘鏇糧構鹹糧顧) 更多 | - | 2015-07-14 | ||
(Phase I Dose Finding - Level 1 5mg) | 齋網衊簾壓窪簾網構壓(艱獵顧鑰淵糧壓願糧衊) = 艱醖鑰壓構觸窪繭衊簾 衊獵齋壓窪遞鏇窪艱窪 (網窪衊願顧觸齋廠構糧, 鏇積齋觸鬱網襯構願積 ~ 鏇網壓齋衊鑰築遞餘蓋) 更多 |
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