CEP-1347(CEP-1347) - 药物靶点：MAP3K11_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

MAP3K11

作用机制

MAP3K11抑制剂(丝裂原活化蛋白激酶激酶激酶-11抑制剂)

治疗领域

神经系统疾病内分泌与代谢疾病免疫系统疾病+ [2]

在研适应症-

非在研适应症

阿尔茨海默症哮喘认知障碍+ [2]

原研机构

H. Lundbeck A/S

在研机构-

非在研机构

H. Lundbeck A/SKyowa Hakko Kogyo Co., Ltd.

Cephalon, Inc.

+ [1]

最高研发阶段终止临床3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C33H33N3O5S2

InChIKeySCMLRESZJCKCTC-KMYQRJGFSA-N

CAS号156177-65-0

关联

2

项与 CEP-1347 相关的临床试验

EUCTR2004-002812-27-IS / Not yet recruiting临床2期

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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87

项与 CEP-1347 相关的文献（医药）

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

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.

2023-09-01·European Journal of Medicinal Chemistry

The emerging role of mixed lineage kinase 3 (MLK3) and its potential as a target for neurodegenerative diseases therapies

Review

作者: Recio, Javier ; Moreno, Ricardo ; Gil, Carmen ; Barber, Santiago ; Martinez, Ana

Selective and brain-permeable protein kinase inhibitors are in preclinical development for treating neurodegenerative diseases. Among them, MLK3 inhibitors, with a potent neuroprotective biological action have emerged as valuable agents for the treatment of pathologies such as Alzheimer's, Parkinson's disease and amyotrophic lateral sclerosis. In fact, one MLK3 inhibitor, CEP-1347, reached clinical trials for Parkinson's disease. Additionally, another compound called prostetin/12k, a potent and rather selective MLK3 inhibitor has started clinical development for ALS based on its motor neuron protection in both in vitro and in vivo models. In this review, we will focus on the role of MLK3 in neuron-related cell death processes, neurodegenerative diseases, and the potential advantages of targeting this kinase through pharmacological modulation for neuroprotective treatment.

2023-08-30·Cancers

Antagonizing MDM2 Overexpression Induced by MDM4 Inhibitor CEP-1347 Effectively Reactivates Wild-Type p53 in Malignant Brain Tumor Cells.

Article

作者: Togashi, Keita ; Okada, Masashi ; Mitobe, Yuta ; Kitanaka, Chifumi ; Sonoda, Yukihiko ; Sugai, Asuka ; Nakagawa-Saito, Yurika ; Suzuki, Shuhei

The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study using CEP-1347, an inhibitor of MDM4 protein expression. The effects of CEP-1347, the genetic and/or pharmacological inhibition of MDM2, and their combination on the p53 pathway in malignant brain tumor cell lines expressing wild-type p53 were investigated by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 alone or in combination with MDM2 on inhibition were examined by dye exclusion and/or colony formation assays. The treatment of malignant brain tumor cell lines with CEP-1347 markedly increased MDM2 protein expression, while blocking CEP-1347-induced MDM2 overexpression by genetic knockdown augmented the effects of CEP-1347 on the p53 pathway and cell growth. Blocking the MDM2-p53 interaction using the small molecule MDM2 inhibitor RG7112, but not MDM2 knockdown, reduced MDM4 expression. Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2's interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells.

1

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	加拿大	Cephalon, Inc.	2002-03-01
帕金森病	临床3期	波多黎各	Cephalon, Inc.	2002-03-01
帕金森病	临床3期	波多黎各	Cephalon, Inc.	2002-03-01
帕金森病	临床3期	波多黎各	H. Lundbeck A/S	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
帕金森病	临床3期	波多黎各	H. Lundbeck A/S	2002-03-01
帕金森病	临床3期	加拿大	H. Lundbeck A/S	2002-03-01
哮喘	临床3期	冰岛	-	-
哮喘	临床3期	冰岛	-	-