MK-0752(MK-0752) - 药物靶点：γ-secretase_专利_临床

概要

基本信息

药物类型

小分子化药

别名

L-000891675、MK 0752

靶点

γ-secretase

作用机制

γ-secretase抑制剂(γ-分泌酶复合体抑制剂)

治疗领域

癌症消化系统疾病内分泌与代谢疾病+ [5]

在研适应症-

非在研适应症

晚期乳腺癌晚期癌症阿尔茨海默症+ [10]

原研机构

Merck Sharp & Dohme Corp.

在研机构-

非在研机构

Merck Sharp & Dohme Corp.

Cancer Research UKMerck GmbH

+ [2]

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C21H21ClF2O4S

InChIKeyXCGJIFAKUZNNOR-QCKZDCLWSA-N

CAS号471905-41-6

关联

6

项与 MK-0752 相关的临床试验

NCT01295632 / Completed临床1期

Phase I Parallel Protocol of MK-8669 (Ridaforolimus) + MK-2206 and MK-8669 (Ridaforolimus) + MK-0752 Doublets (MK-MK) in Patients With Advanced Cancer

This is a two part study of the drug MK-8669 (ridaforolimus) given with MK-2206 or MK-0752. In Part A of the study, the preliminary maximum tolerated dose (MTD) of the drug combinations will be found by giving sequentially higher doses of the study drugs. An expansion cohort of participants may be enrolled to confirm the MTD. New cohorts at other dose levels may be enrolled, depending on the rate of dose limiting toxicities (DLTs) in the planned cohorts. In Part B, an assessment of the efficacy of the drug combinations against selected advanced cancers will be made so that a recommended dose to be used in Phase 2 studies (RPTD) can be found. As of 19 July 2012 the MK-0752 arms of the study were fully enrolled and closed to further recruitment. As of 30 November 2012, no additional participants with prostate cancer will be enrolled.

开始日期2011-02-01

申办/合作机构

Merck Sharp & Dohme Corp.

NCT01243762 / Terminated临床1期

Phase I Parallel Arm Study of MK-0646 (Dalotuzumab) + MK-2206, Dalotuzumab + MK-0752, and Dalotuzumab + MK-8669 (Ridaforolimus) Doublets (MK-MK Doublets) in Patients With Advanced Cancer

This is an open-label, two-part study to evaluate the safety and tolerability of combination treatment with dalotuzumab + MK-2206, dalotuzumab + MK-0752, or dalotuzumab + ridaforolimus (MK-8669). Part 1 of the study will determine the dose-limiting toxicities (DLTs) observed after administration of each of the combinations at various doses and define the maximum tolerated dose (MTD) of each combination. Part 2 of the study will assess preliminary anti-tumor activity of these combinations (at MTD) in two groups of participants with selected tumor biomarkers: one group with metastatic or recurrent platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and one group with metastatic or recurrent colorectal cancer. The dalotuzumab + ridaforolimus and dalotuzumab + MK-2206 arms will be enriched with female platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer participants. The dalotuzumab + MK-0752 arm will be enriched with metastatic or recurrent wild-type kirsten rat sarcoma (KRAS) colorectal cancer participants.
The primary hypothesis is that the DLTs observed in adult patients with locally advanced or metastatic solid tumors after administration of each of the MK-MK doublets will be dose-dependent to allow for definition of a MTD within each MK-MK doublet.

开始日期2010-11-22

申办/合作机构

Merck Sharp & Dohme LLC

NCT00803894 / Completed临床1期

A Randomized Clinical Trial to Study the Effects of MK0752 Versus Placebo on Biomarkers in Healthy Young Adult Male Subjects

The purpose of this study is to determine the transcriptional signature of Notch Inhibition by testing hair and blood samples on healthy male volunteers who have received MK0752 vs placebo for possible future biomarkers in the treatment of cancer or Alzheimers Disease

开始日期2008-12-01

申办/合作机构

Merck Sharp & Dohme Corp.

100 项与 MK-0752 相关的临床结果

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100 项与 MK-0752 相关的转化医学

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100 项与 MK-0752 相关的专利（医药）

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25

项与 MK-0752 相关的文献（医药）

2023-12-01·Endocrine, metabolic & immune disorders drug targets

Effect of Notch Signal Pathway on Steroid Synthesis Enzymes in TM3 Cells

Article

作者: Zhang, Hongdan ; Wang, Jing ; Li, Xiao ; Wu, Zaichao ; Wang, Wei ; Zheng, Yuxiang ; Han, Suo ; Zhang, Chunping

Background::

Studies have indicated that the conservative Notch pathway contributes to steroid hormone synthesis in the ovaries; however, its role in hormone synthesis of the testis remains unclear. We have previously reported Notch 1, 2, and 3 to be expressed in murine Leydig cells and that inhibition of Notch signaling caused G0/G1 arrest in TM3 Leydig cells.

Methods::

In this study, we have further explored the effect of different Notch signal pathways on key steroidogenic enzymes in murine Leydig cells. TM3 cells were treated with Notch signaling pathway inhibitor MK-0752, and different Notch receptors were also overexpressed in TM3 cells.

Results::

We evaluated the expression of key enzymes of steroid synthesis, including p450 choles-terol side-chain cleavage enzyme (P450Scc), 3β-hydroxysteroid dehydrogenase (3β-HSD) and steroidogenic acute regulatory protein (StAR), and key transcriptional factors for steroid synthesis, including steroidogenic factor 1 (SF1), GATA-binding protein 4 (GATA4) and GATA6.

Conclusion::

We found the level of P450Scc, 3β-HSD, StAR and SF1 to be decreased after treat-ment with MK-0752, while overexpression of Notch1 up-regulated the expression of 3β-HSD, P450Scc, StAR and SF1. MK-0752 and overexpression of different Notch members had no influ-ence on the expression of GATA4 and GATA6. In conclusion, Notch1 signaling may contribute to the steroid synthesis in Leydig cells through regulating SF1 and downstream steroidogenic en-zymes (3β-HSD, StAR and P450Scc).

2023-11-01·Journal of cancer research and clinical oncology

In vitro antineoplastic effects of MK0752 in HPV-positive head and neck squamous cell carcinoma.

Article

作者: Stoiber, Stefan ; Kadletz-Wanke, Lorenz ; Lein, Alexander ; Haas, Markus ; Brkic, Faris F ; Varatanovic, Sara

PURPOSE:

Gamma-secretase inhibitor MK0752 has shown a high therapeutic potential in different solid malignant tumors. Up to now, its antineoplastic effects were not investigated in head and neck squamous cell carcinoma (HNSCC) and particularly in human-papillomavirus (HPV)-positive tumors.

METHODS:

We conducted cytotoxic, migration, and clonogenic assays in two HPV-negative HNSCC cell lines (Cal27 and FaDu) and one HPV-positive cell line (SCC154). Furthermore, in order to assess the pro-apoptotic effects of MK0752, a Caspase 3/7 Glo assay was performed.

RESULTS:

Our experiments revealed antineoplastic effects of MK0752 in all three cell lines. Strong cytotoxic and antimigratory potential was shown in all cell lines, with strongest effects observed in the HPV-positive cell line. Meanwhile, anticlonogenic effects were only shown in Cal27 and SCC154. Most importantly, MK0752 induced apoptosis solely in HPV-positive SCC154.

CONCLUSIONS:

Our novel findings indicate a therapeutic potential of MK0752 in HPV-positive HNSCC. Indeed, further investigation is needed for validation of our results and for the assessment of the mechanistic background.

2023-01-01·Wiadomosci lekarskie (Warsaw, Poland : 1960)

NEPHROPROTECTIVE EFFECT OF GAMMA-SECRETASE INHIBITOR ON SEPSIS- INDUCED RENAL INJURY IN MOUSE MODEL OF CLP

Article

作者: Mardan, Haider W ; Hadi, Najah R ; Ghafil, Fadha Abdulameer ; Qassam, Heider ; Majeed, Sahar A

The aim: This study was set out to assess the potential protective impact of MK0752 (a gamma secretase inhibitor) on sepsis-induced renal injury through modulation of inflammatory and oxidative stress pathways. Materials and methods: Twenty-four Swiss-albino mice aged between eight and twelve week and weighted twenty to thirty-seven grams were randomly allocated into four groups (n=6 in each group). Sham group (laparotomy without cecal ligation and puncture (CLP), sepsis group (laparotomy with CLP), vehicle-treated group (equivalent volume of DMSO before the CLP), MK0752 treated group (5 mg/kg) single daily dose for three days before the CLP. Blood samples were used to assess the serum levels of urea and creatinine. The kidneys were used to assess tissue levels of the TNF-α, IL-10, IL-6, TNFR1, VEGF, notch1, jagged1 and tissue damage by histopathological analysis. Results: The current study shows that pretreatment with MK0752 ameliorates the renal damage by significantly reducing the proinflammatory cytokines and notch1 signaling. Conclusions: Taken together, these results suggest that MK0752 could be protective against the renal injury induced by sepsis through its ameliorative impact on renal architecture and modulating cytokines and Notch1 singling pathway. Further studies regarding the role of Notch signaling pathways would be worthwhile.

1

项与 MK-0752 相关的新闻（医药）

2023-09-23

·生物探索

胰腺癌化疗耐药的潜在新机制

胰腺癌细胞中广泛激活的Notch信号通路在癌变、化疗耐药和复发中起重要作用。靶向这一途径是一种很有前景的胰腺癌治疗策略。然而，很少有成功的方法被报道，目前使用的这一途径的分子抑制剂表现出有限的临床益处。2023年9月15日，上海交通大学沈柏用、邓侠兴、符达及施昱晟共同通讯在Cell Discovery（IF=34）在线发表题为“A microprotein N1DARP encoded by LINC00261 promotes Notch1 intracellular domain (N1ICD) degradation via disrupting USP10-N1ICD interaction to inhibit chemoresistance in Notch1- hyperactivated pancreatic cancer”的研究论文，该研究鉴定了一个以前未被鉴定的微蛋白，Notch1降解相关调控多肽(N1DARP)，由LINC00261编码。N1DARP敲除加速了胰腺癌类器官和LSL-Kras、LSL-Trp53和Pdx1-Cre (KPC)小鼠的肿瘤进展，增强了干细胞特性。在机制上，N1DARP通过竞争性地破坏N1ICD与泛素特异性肽酶10 (USP10)之间的相互作用来抑制规范和非规范Notch1途径，从而促进K11和k48相关的N1ICD多泛素化。为了评估N1DARP的治疗潜力，该研究设计了一种穿透细胞的钉接肽，SAH-mAH2-5，具有与N1DARP相似的螺旋结构，具有显著的物理化学稳定性。SAH-mAH2-5与蛋白酶体介导的N1ICD降解相互作用并促进其降解。在Notch1激活的胰腺癌模型中，SAH-mAH2-5注射剂具有显著的治疗效果，但脱靶和全身不良反应有限。胰腺癌是最恶性的消化道肿瘤之一，与其他主要恶性肿瘤相比预后最差，5年生存率< 10%。只有20%的胰腺癌患者有资格接受手术治疗，而其他患者则必须接受化疗。胰腺导管腺癌（PDAC）以其对标准化疗的难治性耐药性而闻名，这可以归因于其固有的瘤内异质性和高度桥粒增生的肿瘤微环境。最近的证据支持使用在胰腺癌中持续激活的高度保守的信号通路，如Notch，Hedgehog和Wnt信号通路，以确定新的生物标志物和治疗靶点。Notch通路在多种人类癌症中都很活跃，包括乳腺癌、结肠直肠癌、肺癌、前列腺癌、胶质母细胞瘤和胰腺癌。在细胞系和基因突变小鼠模型中，Notch信号与胰腺肿瘤的发生、进展和耐药性呈正相关。在临床前模型中，通过旨在影响HES1转录功能的小分子(JI051和JI130)和靶向Notch通路的天然药物，如姜黄素、染料木素、槲皮素和萝卜硫素，药物抑制Notch信号传导，减缓肿瘤的增殖和侵袭，诱导肿瘤内凋亡，并增强化疗作用。值得注意的是，阻断Notch切割的γ-分泌酶抑制剂，包括PF-03084014、MK-0752和RO4929097，已在临床研究中用于治疗转移性胰腺癌。遗憾的是，没有观察到明显的缓解，可能是由于Notch1和其他家族成员的双重或泛notch抑制，导致其他信号通路的代偿激活。这表明，特异性靶向单个Notch家族成员或其他配体，如抗体或阻断蛋白质相互作用的蛋白质亚基，是一种很有希望的破坏Notch信号传导的方法。最近，一项针对转移性胰腺癌的II期研究显示，tarextumab(一种抑制Notch2/3受体的全人源IgG2抗体)联合吉西他滨(GEM)和紫杉醇治疗，在患者中显示出显著的缓解和耐受性，这表明针对特定Notch家族成员的治疗具有良好的前景。机理模式图（图源自Cell Discovery ）Notch是一个短寿命蛋白家族，主要通过泛素-蛋白酶体系统进行快速降解，其各种成分可积极或消极地调节Notch1的稳定性。这表明促进泛素介导的Notch家族成员降解可能是靶向Notch激活癌症的一种有希望的策略。USP10是一种序列高度保守的去泛素化酶，是参与肿瘤发生的p53负调控因子。USP10通过去泛素化多种蛋白使癌细胞产生化学耐药。N1ICD在USP10介导的生物过程中起着至关重要的作用，如细胞发育、血管生成和心功能障碍。因此，靶向USP10-N1ICD相互作用可能是Notch1过度激活癌症的潜在抗肿瘤策略。长链非编码RNA(lncRNAs)可作为信号、诱饵、向导和支架。最近的证据表明，在多种生物过程中发挥关键作用的功能肽是由lncRNAs中的短开放阅读框(ORFs)编码的。然而，在胰腺癌中很少有lncRNAs编码肽及其在肿瘤发生和肿瘤进展中的作用的报道。该研究通过RNA测序和核糖体分析鉴定了一种以前未被鉴定的多肽，N1DARP，由LINC00261编码，作为一种新的肿瘤抑制和化疗增敏剂，用于胰腺癌治疗，它通过干扰USP10-N1ICD相互作用而起作用。该研究还评估了利用N1DARP衍生的修饰钉状肽SAH-mAH2-5靶向N1DARP的治疗潜力，该修饰钉状肽干扰了USP10-N1ICD相互作用并抑制Notch1激活的胰腺癌的肿瘤生长，从而为如何靶向N1DARP - n1icd相互作用以开发精确和个性化的胰腺癌治疗提供了见解。综上所述，这些发现证实了N1DARP通过调节USP10-Notch1致癌信号作为肿瘤抑制因子和化学增敏剂，并提出了一种针对N1DARP-N1ICD相互作用的治疗Notch1激活胰腺癌的有希望的治疗策略。文章来源“iNature”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

临床结果临床研究

100 项与 MK-0752 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12852

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
晚期乳腺癌	临床2期	美国	Merck Sharp & Dohme Corp.	2008-03-01
局部晚期乳腺癌	临床2期	美国	Merck Sharp & Dohme Corp.	2008-03-01
转移性乳腺癌	临床2期	美国	Merck Sharp & Dohme Corp.	2008-03-01
乳腺癌	临床2期	-	National Cancer Institute	-
乳腺癌	临床2期	-	Merck Sharp & Dohme Corp.	-
胰腺癌	临床2期	-	Merck Sharp & Dohme Corp.	-
胰腺癌	临床2期	-	National Cancer Institute	-
晚期癌症	临床1期	-	Merck Sharp & Dohme LLC	2010-11-22
中枢神经系统肿瘤	临床1期	美国	National Cancer Institute	2008-07-01
慢性淋巴细胞白血病	临床1期	-	Merck Sharp & Dohme Corp.	2005-02-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01243762 (0646-027, CTgov)	临床1期	晚期癌症	47	MK-0752+dalotuzumab (Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg)	網簾淵獵簾願廠襯膚鑰(簾窪膚構願淵廠網鹽壓) = 積膚構範範鹽鹽襯簾膚鹹製遞壓糧範鑰構鬱壓 (憲壓衊膚選願鑰艱壓鬱, 願膚構鏇夢鹹製襯艱觸 ~ 構簾膚獵觸糧繭膚蓋選) 更多	-	2017-10-30
NCT01243762 (0646-027, CTgov)	临床1期	晚期癌症	47	MK-0752+dalotuzumab (Dalotuzumab 10 mg/kg + MK-0752 1800 mg)	網簾淵獵簾願廠襯膚鑰(簾窪膚構願淵廠網鹽壓) = 襯顧鬱鏇鏇齋鬱憲選壓鹹製遞壓糧範鑰構鬱壓 (憲壓衊膚選願鑰艱壓鬱, 窪鑰鬱廠襯鬱窪餘積醖 ~ 觸鏇齋鬱範鑰餘範鏇積) 更多	-	2017-10-30
NCT01295632 (8669-049, Pubmed \| Eur J Cancer Care (Engl)) 人工标引	临床1期	晚期恶性实体瘤	28	ridaforolimus+MK-0752	鹽鹹願鏇夢繭艱構廠憲(遞築餘繭淵網觸襯壓鑰) = 繭願遞淵鹹餘製餘醖襯獵衊淵繭齋積鹹憲淵鏇 (壓觸憲遞淵製網積鹹顧 ) 更多	积极	2015-09-01
NCT00572182 (Pubmed \| Childs Nerv Syst) 人工标引	临床1期	癌症	10	MK-0752	淵鑰鬱網選夢襯齋蓋觸(餘憲夢壓願壓範遞築齋) = One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. 鏇願襯壓糧衊遞鬱築醖 (艱淵製衊廠觸齋構構夢 )	积极	2015-08-01
NCT00645333 (CTgov)	临床1/2期	局部晚期乳腺癌 \| 转移性乳腺癌 \| 晚期乳腺癌	30	MK-0752+Docetaxel (MK-0752 and Docetaxel)	遞醖築遞築遞製憲願製(鏇遞積範窪鬱齋積鏇憲) = 鹽構選淵構憲願襯廠遞顧構夢鬱鏇艱遞壓鹹憲 (膚憲製製願築築選願衊, 選築構製醖淵繭憲獵鬱 ~ 鏇選憲顧夢廠壓積願膚) 更多	-	2014-04-04
NCT00645333 (CTgov)	临床1/2期	局部晚期乳腺癌 \| 转移性乳腺癌 \| 晚期乳腺癌	30	pegfilgrastim+MK-0752+docetaxel (MK-0752)	憲壓鏇鏇範遞鏇蓋襯衊(鹹獵齋鬱餘網繭鹹衊蓋) = 繭醖積網廠醖襯壓製製願淵鹽鏇網簾觸憲觸窪 (顧繭憲醖窪願觸製鬱選, 鹽遞衊遞醖壓窪鬱鹽顧 ~ 鏇遞鏇夢憲積憲廠獵壓) 更多	-	2014-04-04
ASCO2006	临床1期	T-ALL/LBL \| 白血病	8	MK-0752	獵觸願鏇築繭窪鏇鏇憲(廠壓構築齋夢醖鹹鹽廠) = 築遞蓋鏇鹽製鑰糧鏇鹽繭膚鬱網鏇鏇選壓選顧 (願鬱齋鏇鑰鑰築淵醖糧 ) 更多	-	2006-06-20