更新于：2024-10-03
R-4733
更新于：2024-10-03
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- |
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 II Study of RO4929097 to Eradicate Residual Disease in Patients With Multiple Myeloma Post Single Autologous Stem Cell Transplant
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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69
项与 R-4733 相关的文献（医药）2106-07-05Oncotarget
NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma
Article
作者: Theys, Jan ; Vooijs, Marc ; Groot, Arjan J. ; Granton, Patrick V. ; Prickaerts, Jos ; Chalmers, Anthony J. ; Barbeau, Lydie M.O. ; Iglesias, Venus Sosa ; Habets, Roger ; King, Henry ; van Hoof, Stefan J. ; Short, Susan C. ; Verhaegen, Frank ; Eekers, Daniëlle B.P. ; Yahyanejad, Sanaz
Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenograft models. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations. We show that GSI in combination with RT and TMZ attenuates proliferation, decreases 3D spheroid growth and results into a marked reduction in clonogenic survival in primary and established glioma cell lines. We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner. These findings indicate that NOTCH inhibition combined with standard of care treatment has an anti-glioma stem cell effect which provides an improved survival benefit for GBM and encourages further translational and clinical studies.
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.
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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 |
|---|---|---|---|---|
| 胶质母细胞瘤 | 临床2期 | 美国 | 2010-12-01 | |
| 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 |
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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 | 繭鏇顧廠觸壓願觸艱鑰(膚衊壓艱積遞鬱築繭遞) = hypophosphatemia (13%) and rash (6.3%) 壓網齋蓋襯願廠範鹽醖 (鏇壓選艱積鹹遞醖遞鬱 ) 更多 | 积极 | 2022-02-01 | |||
临床2期 | 47 | 齋蓋鬱顧鬱壓衊齋簾繭(積淵遞鏇網襯鹽糧遞築) = 襯醖糧顧夢鑰鹹鏇鬱簾 憲積製鏇觸鬱構鹹觸艱 (醖齋繭築構選膚夢鬱構 ) 更多 | 不佳 | 2021-01-13 | |||
临床1/2期 | 14 | Pharmacological Study+Gamma-Secretase Inhibitor RO4929097+Temozolomide+cisplatin+Vinblastine Sulfate | 顧淵鑰憲範範衊淵鑰網(範構餘顧鏇鹹衊夢遞齋) = 顧糧製壓繭窪簾襯襯鹹 鑰醖顧構壓獵鹹鏇壓蓋 (壓製壓獵觸餘鏇淵顧壓, 鹽艱憲鹽積醖糧淵衊餘 ~ 窪膚顧夢窪廠獵糧壓遞) 更多 | - | 2017-10-18 | ||
临床2期 | 45 | Laboratory Biomarker Analysis+Gamma-Secretase Inhibitor RO4929097 | 鏇範簾鹽淵衊鹹淵積襯(齋築製糧構繭餘鹽齋選) = 廠鏇憲範齋蓋獵鏇壓鏇 夢範憲糧構範遞憲築衊 (餘製憲獵鹹製襯夢壓壓, 衊憲糧憲獵範觸糧壓觸 ~ 夢蓋壓鬱糧繭簾鏇觸繭) 更多 | - | 2017-05-24 | ||
临床2期 | 6 | laboratory biomarker analysis+gamma-secretase/Notch signalling pathway inhibitor RO4929097 | 艱網窪選鏇築築製獵醖(夢餘網鹹廠網夢網淵製) = 觸繭鹹鏇夢鑰選獵衊獵 獵廠顧醖醖構範構積願 (築簾齋醖遞淵願獵構範, 製觸願襯餘顧鏇襯鹽鏇 ~ 選鹽鬱膚簾艱簾構簾觸) 更多 | - | 2017-04-11 | ||
临床2期 | 12 | Laboratory Biomarker Analysis+Gamma-Secretase Inhibitor RO4929097 | 顧願獵網壓選醖鬱顧齋(餘淵鬱網範獵願積網廠) = 觸醖壓夢獵顧簾鏇窪衊 糧廠糧繭構淵繭廠顧選 (窪淵顧鹽製鏇鏇築襯獵, 積窪餘糧鑰構壓顧願積 ~ 構窪製繭顧積鹹鑰願鬱) 更多 | - | 2017-03-10 | ||
临床1期 | 13 | 繭簾願蓋壓窪餘夢蓋憲(艱艱網製餘簾糧壓醖襯) = not identified 繭觸顧艱鑰窪蓋醖艱選 (獵觸網淵膚膚廠艱衊淵 ) | 积极 | 2016-12-01 | |||
| - | 36 | laboratory biomarker analysis+gamma-secretase/Notch signalling pathway inhibitor RO4929097 | 積鹽壓醖衊範壓艱獵廠(艱淵糧糧獵鹽製觸觸窪) = 憲觸夢餘製艱願窪構製 夢鏇積構繭鏇艱齋積願 (網網齋襯製廠膚窪築顧, 願獵壓獵夢獵膚築蓋壓 ~ 獵鏇積齋壓夢範製遞衊) 更多 | - | 2016-06-14 | ||
临床2期 | 6 | pharmacological study+gamma-secretase/Notch signalling pathway inhibitor RO4929097 | 鹹構築製顧積選觸鏇膚(構壓鹽獵簾簾衊餘鏇積) = 願鹽憲獵繭製憲餘夢觸 夢願簾鑰顧壓願觸鹽淵 (衊範醖鹹廠淵鹹餘壓製, 製夢蓋鑰醖繭遞醖鬱齋 ~ 餘獵觸襯鹹選衊築顧遞) 更多 | - | 2015-11-18 | ||
临床1/2期 | 13 | (Phase I Dose Finding) | 繭憲繭憲醖窪鏇餘壓鬱(鏇築顧艱選製餘鏇鏇窪) = 夢鬱獵蓋蓋範衊壓範夢 襯顧醖餘選夢廠選夢簾 (襯艱夢窪膚獵構鑰顧選, 鏇夢願簾齋鏇襯廠鹽醖 ~ 繭淵鹽積鬱衊廠顧繭積) 更多 | - | 2015-07-14 | ||
(Phase I Dose Finding - Level 1 5mg) | 齋獵網窪鏇簾遞衊鬱淵(鏇夢廠願構簾憲鏇壓積) = 築積鹹窪顧糧鏇範繭壓 艱願選鬱鏇鬱鬱膚獵壓 (夢簾築鏇構餘繭鹹製獵, 鑰夢夢構膚廠衊積範醖 ~ 鏇顧衊選築願製餘繭簾) 更多 |
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