A prospective, randomised, double-blind, placebo-controlled, parallel group dose ranging study in asthma patients in Iceland to assess the safety, tolerability and efficacy of the MLK inhibitor, CEP-1347

开始日期2005-05-04

申办/合作机构

deCODE Genetics ehf

NCT00040404

/ Terminated临床2/3期

A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study to Assess the Efficacy and Safety of CEP-1347 in Patients With Parkinson's Disease

The purpose of this study is to establish safety for CEP-1347 and to determine an efficacious dose in the treatment of Parkinson's disease.

开始日期2002-03-01

申办/合作机构

Cephalon, Inc.

[+2]

100 项与 CEP-1347 相关的临床结果

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100 项与 CEP-1347 相关的转化医学

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100 项与 CEP-1347 相关的专利（医药）

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100

项与 CEP-1347 相关的文献（医药）

2025-11-01·ANTICANCER RESEARCH

The MDM4 Inhibitor CEP-1347 Activates Wild-type p53 in Ovarian Clear Cell Carcinoma Cells and Potently Inhibits their Growth

Article

作者: Nakagawa-Saito, Yurika ; Ito, Yasufumi ; Okada, Masashi ; Nagase, Satoru ; Nakamura, Kazuki ; Kitanaka, Chifumi ; Suzuki, Shuhei ; Takenouchi, Senri ; Togashi, Keita ; Sugai, Asuka ; Ohta, Tsuyoshi ; Seino, Manabu

BACKGROUND/AIM:

Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer, in which TP53 mutation is uncommon in contrast to high-grade serous carcinoma, the predominant subtype. Therefore, the functional reactivation of p53 is an attractive therapeutic opportunity for this subtype of ovarian cancer. Nevertheless, the therapeutic potential of targeting MDM4, a representative negative regulator of p53, has not yet been reported. In the present study, we investigated the impact of CEP-1347, an MDM4 inhibitor with a known safety profile in humans, on p53 pathway activity and the growth of OCCC cells.

MATERIALS AND METHODS:

The effects of CEP-1347 as well as the knockdown of MDM4 or p53 on the mRNA and/or protein expression of components of the p53 pathway, including MDM4, in human OCCC cell lines with and without p53 mutation were examined by RT-PCR and western blot analyses. Dye exclusion and colony formation assays were used to examine the effects of CEP-1347 on cell growth.

RESULTS:

CEP-1347 decreased MDM4 and increased p53 protein expression, and also induced the expression of p21, a CDK inhibitor, in a p53-dependent manner in OCCC cells with wild-type p53. In these cells, the knockdown-mediated inhibition of MDM4 expression increased the expression of p53 and p21. Furthermore, CEP-1347 potently inhibited the growth and clonogenic survival of OCCC cells without exhibiting toxicity in normal cells at clinically relevant concentrations.

CONCLUSION:

The present results suggest the potential of targeting MDM4 with CEP-1347 as a therapeutic approach for the treatment of OCCC with wild-type p53.

2025-11-01·ANTICANCER RESEARCH

Senolytic Elimination of Senescent Ovarian Clear Cell Carcinoma Cells Induced by CEP-1347 With the BH3 Mimetic Navitoclax

Article

作者: Nakagawa-Saito, Yurika ; Ito, Yasufumi ; Okada, Masashi ; Takenouchi, Senri ; Suzuki, Shuhei ; Togashi, Keita ; Kitanaka, Chifumi ; Ohta, Tsuyoshi ; Seino, Manabu ; Nagase, Satoru ; Mitobe, Yuta ; Nakamura, Kazuki ; Sugai, Asuka

BACKGROUND/AIM:

Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer characterized by infrequent TP53 mutations. We recently reported that the MDM4 inhibitor CEP-1347 effectively activated the p53 - p21 axis and inhibited the proliferation of OCCC cells with wild-type TP53. We also recently found that CEP-1347 induced senescence-like phenotypes in glioma stem cells and sensitized them to senolytics, such as BH3 mimetics represented by navitoclax. In the present study, we investigated whether CEP-1347 induced senescence-like phenotypes in OCCC cells and if combinations with BH3 mimetics enhanced the anti-cancer activity of CEP-1347 by promoting senolysis in OCCC cells.

MATERIALS AND METHODS:

Senescence-like phenotypes were analyzed using microscopy, flow cytometry, and western blotting. Combined effects with senolytics were evaluated using cell death assays, colony formation assays, and western blot analysis.

RESULTS:

CEP-1347 induced cellular senescence in OCCC cells with wild-type TP53. Furthermore, in combination with senolytics, particularly navitoclax, CEP-1347 strongly induced apoptotic death in these OCCC cells under conditions that were not toxic to normal cells.

CONCLUSION:

CEP-1347 induced cellular senescence in OCCC cells with wild-type TP53. The combination of CEP-1347 with senolytics, such as navitoclax, represents a rational strategy to ensure the selective elimination of senescent OCCC cells and enhance therapeutic efficacy.

2024-09-12·JOURNAL OF MEDICINAL CHEMISTRY

Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC

Article

作者: Sabbasani, Venkata R. ; Mehlich, Dawid ; Truong, Vi Nguyen-Phuong ; Marusiak, Anna A. ; Brognard, John ; Karpińska, Kamila ; Wróbel, Katarzyna ; Torres-Ayuso, Pedro ; Serwa, Remigiusz ; Łomiak, Michał ; Swenson, Rolf E.

Triple-negative breast cancer (TNBC) is associated with poor prognosis because of the lack of effective therapies. Mixed-lineage protein kinase 3 (MLK3) is a protein that is often upregulated in TNBC and involved in driving the tumorigenic potential of cancer cells. Here, we present a selective MLK3 degrader, CEP1347-VHL-02, based on the pan-MLK inhibitor CEP1347 and a ligand for E3 ligase von Hippel-Lindau (VHL) by employing proteolysis-targeting chimera (PROTAC) technology. Our compound effectively targeted MLK3 for degradation via the ubiquitin-proteasome system in several cell line models but did not degrade other MLK family members. Furthermore, we showed that CEP1347-VHL-02 robustly degraded MLK3 and inhibited its oncogenic activity in TNBC, measured as a reduction of clonogenic and migratory potential, cell cycle arrest, and the induction of apoptosis in MDA-MB-468 cells. In conclusion, we present CEP1347-VHL-02 as a novel MLK3 degrader that may be a promising new strategy to target MLK3 in TNBC.

项与 CEP-1347 相关的新闻（医药）

2024-10-16

·精准药物

【JMC】一种新型选择性降解MLK3降解剂

近日，来自波兰科学院的Remigiusz Serwa团队和来自美国国立卫生研究院的Rolf E. Swenson教授在《Journal of Medicinal Chemistry》上合作发表了一篇题为《Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC》的文章。该研究基于pan-MLK抑制剂CEP1347和E3连接酶VHL (von Hippel-Lindau)的配体，利用靶向蛋白水解嵌合体(PROTAC)技术，开发了一种可选择性降解混合谱系激酶3（MLK3）的化合物，研究发现化合物CEP1347-VHL-02在几种细胞系模型中可通过泛素-蛋白酶体系统有效地靶向MLK3降解，而不降解其他MLK家族成员。此外，他们发现CEP1347-VHL-02在有效降解MLK3的同时也可抑制其在TNBC中的致癌活性，进一步认为这种新型MLK3降解剂CEP1347-VHL-02在三阴性乳腺癌（TNBC）的治疗中具有潜在应用价值。在过去的几十年里，研究人员们已经设计了几种小分子抑制剂来靶向MLK3和其他MLK家族成员，如CEP1347等，已被作为新的研究抗癌药物，但这些化合物的使用受到其低特异性的限制。针对此类抑制剂的使用缺陷，研究者们以CEP1347为药效团，设计并合成了8种由CEP1347和E3泛素连接酶VHL配体组成的PROTACs，并偶联了不同的连接体(CEP1347-VHL-01−CEP1347-VHL-08)。图 1 为了确定实现有效降解MLK3的最佳连接体长度，研究者们利用免疫印迹检测多西环素(DOX)诱导的MLK3过表达(分别为A375_MLK3和HCC1806_MLK3)的A375和HCC1806细胞株，评估合成的PROTACs化合物对MLK3的降解效率，其中发现化合物CEP1347-VHL-02可以实现对MLK3的有效降解。图 2 接下来，他们使用蛋白酶体抑制剂Carfilzomib处理HCC1806_MLK3细胞，确认了CEP1347-VHL-02是通过泛素-蛋白酶体途径实现对MLK3的降解作用(图3A)。此外，研究者们通过动力学实验(图3B,C)、蛋白质组学分析（图3E）以及免疫印迹分析实验（图3G），进一步验证了CEP1347-VHL-02对MLK3的选择性降解效果。图 3 为了验证CEP1347-VHL-02是否在该激酶高表达的细胞系中降解内源性MLK3，他们使用了乳腺癌细胞系MCF-7(ER+亚型)和MDA-MB-468(TNBC亚型)进行了额外实验，这些实验均证实CEP1347-VHL-02在两种细胞系中都具有最佳的降解能力（图4）。图 4 最后，他们对MCF-7和MDAMB-468细胞系进行了一系列表型分析。首先，他们观察到经CEP1347-VHL-02处理的MDA-MB-468细胞的克隆生成潜力显著降低（图5A右），而在MCF-7细胞系中没有观察到这种作用（图5A左）。此外，流式细胞术分析结果显示MDA-MB-468细胞增殖降低可能是由CEP1347-VHL-02处理后G2/M期细胞周期阻滞引起的(图5B)，同时研究者们观察到PROTAC对MDA-MB-468细胞凋亡产生了一定的诱导作用(图5C)。这些结果均表明，由于MLK3的降解，选择性地降低了TNBC细胞的致瘤性和侵袭潜力，其中MLK3起致瘤作用。图 5 总之，研究团队证实了基于PROTAC技术合成的化合物CEP1347-VHL-02可实现对癌细胞系中MLK3的快速和选择性降解。该项研究为MLK3在癌症治疗中的选择性靶向提供了新的机会，并为开发下一代MLK3及相关激酶的降解物铺平了道路。本文作者：CY 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

蛋白降解靶向嵌合体

100 项与 CEP-1347 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05403

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
帕金森病	临床3期	美国	H. Lundbeck A/S	2002-03-01
帕金森病	临床3期	美国	Cephalon, Inc.	2002-03-01
帕金森病	临床3期	加拿大	H. Lundbeck A/S	2002-03-01
帕金森病	临床3期	加拿大	Cephalon, Inc.	2002-03-01
哮喘	临床2期	美国	deCODE Genetics ehf	2005-05-18
神经系统疾病	临床前	日本	Kyowa Hakko Kogyo Co., Ltd.	1997-06-06
认知障碍	临床前	美国	Cephalon, Inc.	-