奥瑞布林(Ombrabulin Hydrochloride) - 药物靶点：Tubulin_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Ombrabulin、Ombrabulin hydrochloride (JAN)、AC 7700

+ [7]

靶点

Tubulin

作用方式

抑制剂

作用机制

微管蛋白抑制剂

治疗领域

肿瘤其他疾病内分泌与代谢疾病+ [2]

在研适应症-

非在研适应症

晚期恶性实体瘤局部晚期软组织肉瘤转移性非小细胞肺癌+ [2]

原研机构

Ajinomoto Co., Inc.

在研机构-

非在研机构

Sanofi

权益机构

Ajinomoto Co., Inc.Aventis SA

最高研发阶段无进展临床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/序列

分子式C21H27ClN2O6

InChIKeyUQNRTPFLTRZEIM-MRWUDIQNSA-N

CAS号253426-24-3

关联

11

项与奥瑞布林相关的临床试验

NCT01332656

/ Completed临床2期

A Phase 2, Multi-Center, Double-Blind, Placebo Controlled, Randomized Study of Ombrabulin in Patients With Platinum-Sensitive Recurrent Ovarian Cancer Treated With Carboplatin/Paclitaxel

Primary Objective:
- To demonstrate an improvement in Progression-Free Survival (PFS) for Ombrabulin versus placebo in patients with platinum-sensitive recurrent ovarian cancer (OC) treated with paclitaxel and carboplatin.
Secondary Objectives:
* To compare the overall survival (OS) between the 2 treatment arms
* To compare the objective response rate (RR) between the 2 treatment arms

开始日期2011-05-01

申办/合作机构

Sanofi

NCT01263886

/ Completed临床2期

A Multinational, Randomized, Double Blind, Controlled Phase II Trial of Ombrabulin With Taxane and Platinum Combination Administered Every Three Weeks, in First Line Treatment of Patients Metastatic Non-small Cell Lung Cancer

Primary Objective:
* To demonstrate progression free survival (PFS) improvement for ombrabulin compared to placebo, in combination with taxane and platinum, as first line treatment for patients with metastatic non-small cell lung cancer (NSCLC).
Secondary Objective:
* To determine overall survival (OS), overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria, safety, and evaluate potential biomarkers, pharmacokinetic (PK) analysis of ombrabulin and its main metabolite, RPR258063, using a population approach.

开始日期2011-02-01

申办/合作机构

Sanofi

NCT01293630

/ Completed临床1期

An Open-label, Dose-escalation, Safety and Pharmacokinetics Phase I Study of Ombrabulin in Combination With Paclitaxel and Carboplatin Every 3 Weeks in Patients With Advanced Solid Tumors

The primary objective of the study is to determine the maximum tolerated dose (MTD) based on the incidence of dose limiting toxicity (DLT) and the maximum administered dose (MAD) of ombrabulin combined with paclitaxel and carboplatin administered every 3 weeks in patients with advanced solid tumors.
Secondary Objectives:
* To assess the overall safety profiles of the combination therapy
* To characterize the pharmacokinetic profile of ombrabulin, its active metabolite RPR 258063, paclitaxel, and carboplatin when used in combination
* To document the objective tumor response

开始日期2011-01-01

申办/合作机构

Sanofi

100 项与奥瑞布林相关的临床结果

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100 项与奥瑞布林相关的转化医学

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100 项与奥瑞布林相关的专利（医药）

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57

项与奥瑞布林相关的文献（医药）

2020-12-01·MEDICINAL CHEMISTRY RESEARCH

Synthesis, biological evaluation and molecular docking studies of Combretastatin A-4 phosphoramidates as novel anticancer prodrugs

作者: Zhang, Shaowu ; Wu, Fanhong ; Pang, Wan ; Wu, Fulong ; Li, Tang ; Wu, Jingjing ; Liu, Yangyang

A new series of CA4P analogs (5a-g, 6a-g) has been designed and effectively synthesized via a one-pot reaction from Combretastatin A-4/Erianin, com. available amino acid esters and Ph dichlorophosphate.To establish new candidates with anticancer activity, the in vitro antiproliferative effect of these compounds was measured by the CCK8 method on different cancer cell lines such as human liver carcinoma (HepG2), cervical cancer (HeLa) and colorectal carcinoma (HCT-116).The structure-activity relationships between CA4P outgrowth-promoting activity and its analogs suggested that the biaryl structure linked with double bond in Part A and the steric effect at the position α-carbon atom in the amino acid ester moiety (Part B) are essential for affecting the in vitro proliferation inhibitory activity of CA4P analogs.Addnl., the results of biol. activity and mol. docking simulation showed that the vast majority of these novel Phosphoramidate derivatives exhibited potent anti-cancer activities. [graphic not available: see fulltext].

2020-10-01·Bioorganic chemistry2区 · 化学

NQO1-selective activated prodrugs of combretastatin A-4: Synthesis and biological evaluation

2区 · 化学

Article

作者: Li, Yue ; Ma, Xin ; Li, Manping ; Wu, Liqiang ; Zhang, Chong ; Li, Sen ; Qu, Yan

Tumor-specific prodrug treatment renders the exclusive delivery of antitumor agents with the lowest untoward effects. In this work, we reported the synthesis and biological assessment of four NQO1-activatable combretastatin A-4 prodrugs constituted by active drug CA-4, different self-immolating linkers, and NQO1-responsive trigger groups. The in vitro antiproliferative activities showed that prodrug 4 displayed greater selective toxicity toward the tumor cells that overexpressed NQO1, taxol-resistant A549 cells, hypoxia-exposed A549 and HepG2 cells, and incurred lower damage to normal cells in comparison with combretastatin A-4, prodrugs 1, 2, and 3. Moreover, based on a mechanistic study, NQO1 triggered prodrug 4 to effectively liberate the parent drug combretastatin A-4 and kill tumor cells. Furthermore, we also demonstrated that prodrug 4 exerted a stronger anticancer effect and greater safety than combretastatin A-4 under in vivo conditions. Hence, from the above results, NQO1 can be used as a specific delivery system for releasing anticancer agents; besides, prodrug 4 can serve as a candidate lead for developing specific anticancer agents.

2020-06-01·Bioorganic chemistry2区 · 化学

Tubulin inhibitors: Discovery of a new scaffold targeting extra-binding residues within the colchicine site through anchoring substituents properly adapted to their pocket by a semi-flexible linker

2区 · 化学

Article

作者: Abdelhamid, Dalia ; AbdelHafez, El-Shimaa M N ; Maklad, Raed M ; Aly, Omar M

Bis-hydrazides 13a-h were designed and synthesized as potential tubulin inhibitors selectively targeting the colchicine site between α- and β-tubulin subunits. The newly designed ring-B substituents were assisted at their ends by 'anchor groups' which are expected to exert binding interaction(s) with new additional amino acid residues in the colchicine site (beyond those amino acids previously reported to interact with reference inhibitors as CA-4 and colchicine). Conformational flexibility of bis-hydrazide linker assisted these 'extra-binding' properties through reliving ligands' strains in the final ligand-receptor complexes. Compound 13f displayed the most promising computational and biological study results in the series: MM/GBSA binding energy of -62.362 kcal/mol (extra-binding to Arg α:221, Thr β:353 & Lys β:254); 34% NCI-H522 cells' death (at 10 µM), IC₅₀ = 0.073 µM (MTT assay); significant cell cycle arrest at G2/M phase; 11.6% preG1 apoptosis induction and 83.1% in vitro tubulin inhibition (at concentration = IC₅₀). Future researchers in bis-hydrazide tubulin inhibitors are advised to consider the 2-chloro-N-(4-substituted-phenyl)acetamide derivatives as compound 13f due to extra-binding properties of their ring B.

1

项与奥瑞布林相关的新闻（医药）

2025-02-21

·今日头条

晚期实体瘤治疗新突破：中山大学1期研究揭示口服血管破坏剂的潜力

点击蓝字关注我们【导读】 DX1002是一种口服血管破坏剂，在临床前研究中显示出有希望的结果，导致各种动物模型中的肿瘤脉管系统破坏和异种移植肿瘤坏死。 2025年2月18日，中山大学肿瘤防治中心的研究团队在期刊《Cell Reports Medicine》上合作发表了题为“First-in-human phase 1 study of an orally bioavailable vascular-disrupting agent DX1002 in patients with advanced solid tumors”的研究论文。研究结果表明， DX1002在晚期实体瘤患者中表现出良好的安全性和早期抗肿瘤活性，具有独特的肿瘤血管靶向性，且与化疗联合治疗显示出潜在协同效应，值得进一步临床研究。 https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00042-4 01 研究背景在1990年代，血管靶向疗法（VTT）的使用已被确立为一种可行性，VTT有两种主要类型，即血管破坏剂（VDA）和血管生成抑制剂（AIA）。AIAs可以抑制肿瘤血管的形成，而VDAs可以导致现有肿瘤血管的快速和选择性闭合，并导致缺血和广泛出血性坏死。先前的早期临床试验表明，VDA具有可控的安全性和初步的抗肿瘤疗效。VDA包括两个主要类别，即单克隆抗体（如Tarvacin）和小分子VDA。小分子VDA可以根据其分子结构进一步分为秋水仙碱、CA4类似物（如CA4P、ombrabulin、ZD6126、OXi4503、BNC105P、DX1002和C118P）和类黄酮药物（例如DMXAA和MN029）。在动物模型中，这些药物已显示出有希望的抗肿瘤作用。其中一些，包括CA4P、ombrabulin和DMXAA （ASA404），已进入3期试验。然而，其他研究的进展受到阻碍，许多研究仍处于早期临床阶段或已被终止。因此，尽管具有潜力，但尚未有VDA获得抗肿瘤治疗的批准。CA4P是最具代表性的VDA之一，但CA4P的缺陷如分子结构不稳定、靶向作用对肿瘤血管的选择性差，以及对心血管系统和周围神经的毒性等极大地限制了其应用。图形摘要 02 抗肿瘤功效所有17例入组患者均可评估抗肿瘤反应。其中12例患者达到SD，其余5例患者主要对DX1002耐药，总体疾病控制率（DCR）为70.6%。未观察到完全或部分反应；因此，客观缓解率为0%，中位进展时间（TTP）为2.70个月。600mg组中的1例NSCLC患者（患者10）达到SD并持续6.5个月，直到撤回知情同意书并停止治疗。该患者的目标病灶总和仅增加了4.1%。此外，团队选择了1名患者（患者01），其肿瘤病灶适合用对比增强超声（CEUS）观察，并记录了血供的变化。该患者实现了4.5个月的TTP，据观察，随着DX1002给药而出现空腔和坏死，而血液供应显著减少。 CEUS观察到的DX1002药物治疗后，典型肿瘤病灶的血供变化。 03 总结 1. DX1002的安全性和耐受性：在首次人体1期临床试验中，DX1002在50-600mg剂量范围内每日1次给药是安全且耐受性良好的，最大耐受剂量（MTD）为600mg。未观察到剂量限制性毒性（DLT），且与其他血管破坏剂（VDA）相比，DX1002未引起心脏和周围神经毒性，显示出更好的安全性。 2. DX1002的抗肿瘤活性：尽管未观察到完全缓解（CR）或部分缓解（PR），但12例患者达到疾病稳定（SD），总体疾病控制率（DCR）为70.6%。DX1002在临床前研究中显示出破坏肿瘤血管并导致肿瘤组织坏死的能力，但肿瘤周围残留的活细胞可能限制了其作为单一疗法的抗肿瘤活性。 3. DX1002的独特机制： DX1002通过在CA4二苯乙烯结构的双键位置引入羧基，增强了稳定性，并显示出对肿瘤血管的选择性破坏，而不伤害正常血管，表明其具有更好的安全性和靶向性。 4. 联合治疗的潜力：临床前研究表明，DX1002与化疗联合使用可增强抗肿瘤效果。3例患者在DX1002治疗后接受后续治疗（如化疗）表现出部分缓解（PR），提示DX1002可能使肿瘤对化疗重新敏感，支持其在联合治疗中的进一步研究。 5. 未来研究方向：基于1期试验的结果，DX1002的推荐2期剂量（RP2D）为每日1次600mg，连续21天给药。2期临床试验（CTR20200996）已启动，进一步评估DX1002单药及与化疗联合治疗的疗效和安全性。参考资料： 1.Pettit, G.R. ∙ Singh, S.B. ∙ Hamel, E. ... Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4 Experientia. 1989; 45:209-211 2.Pettit, G.R. ∙ Singh, S.B. ∙ Boyd, M.R. ... Antineoplastic Agents. 291. Isolation and Synthesis of Combretastatins A-4, A-5, and A-6 J. Med. Chem. 1995; 38:1666-1672 [Erratum to document cited in CA122:290568] 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛点击对应文字查看详情

临床3期临床1期临床结果

100 项与奥瑞布林相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09787	奥瑞布林	-	DB12882

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
局部晚期软组织肉瘤	临床3期	美国	Sanofi	2008-06-01
局部晚期软组织肉瘤	临床3期	比利时	Sanofi	2008-06-01
局部晚期软组织肉瘤	临床3期	巴西	Sanofi	2008-06-01
局部晚期软组织肉瘤	临床3期	法国	Sanofi	2008-06-01
局部晚期软组织肉瘤	临床3期	匈牙利	Sanofi	2008-06-01
局部晚期软组织肉瘤	临床3期	印度	Sanofi	2008-06-01
局部晚期软组织肉瘤	临床3期	意大利	Sanofi	2008-06-01
局部晚期软组织肉瘤	临床3期	塞尔维亚	Sanofi	2008-06-01
局部晚期软组织肉瘤	临床3期	西班牙	Sanofi	2008-06-01
局部晚期软组织肉瘤	临床3期	英国	Sanofi	2008-06-01

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临床结果

适应症

分期

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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


NCT01095302 (Pubmed \| Jpn J Clin Oncol) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	11	docetaxel+cisplatin+ombrabulin	願淵襯蓋憲獵衊構膚獵(糧鹽廠壓鏇餘餘繭製襯) = 顧網鹹製鏇鹽膚醖鬱獵願製構淵衊壓繭窪觸憲 (夢簾願憲壓憲窪壓鏇築 ) 更多	不佳	2018-04-01
NCT00968916 (Pubmed \| Cancer Chemother Pharmacol)	临床1期	晚期恶性实体瘤	15	Ombrabulin 15.5 mg/m(2)	齋夢顧淵觸築襯獵鑰襯(糧糧蓋壓簾選願鹹觸憲) = 夢鬱構願鏇廠衊獵願廠廠積餘網淵艱憲網積廠 (鬱繭衊繭蓋遞獵醖鹹簾 )	-	2014-03-01
NCT01293630 (ESMO2013) 人工标引	临床1期	晚期恶性实体瘤	18	Paclitaxel+Carboplatin+Ombrabulin (dose-escalation)	糧襯築壓網簾願膚積願(鬱選壓鏇窪糧築遞鏇廠) = ombrabulin 35 mg/m2, PTX 200 mg/m2 and CBDCA AUC6 遞繭艱鹽壓壓餘膚艱艱 (鹹蓋獵餘簾積築網觸遞 ) 更多	积极	2013-11-01
NCT01193595 (ASCO2013)	临床1期	HR阳性/HER2低表达实体瘤	39	Ombrabulin	廠築遞衊製齋顧觸積構(繭衊遞衊獵糧鬱衊襯築) = 1/39, 3% 選簾壓廠憲遞廠壓構憲 (鬱顧願醖範夢衊醖淵窪 ) 更多	-	2013-05-20
				Bevacizumab
NCT01332656 (Opsalin, ASCO2013)	临床2期	铂敏感性卵巢癌	154	Ombrabulin 35 mg/m²	遞鹽齋糧壓顧觸鑰積鑰(繭壓製鬱願構憲壓艱顧) = 構構顧鏇鹹壓鏇鹹構艱淵憲範構獵夢網願選遞 (網簾餘觸範鏇願製膚淵 ) 更多	不佳	2013-05-20
				Placebo	遞鹽齋糧壓顧觸鑰積鑰(繭壓製鬱願構憲壓艱顧) = 構廠窪窪艱願壓鹽顧鏇淵憲範構獵夢網願選遞 (網簾餘觸範鏇願製膚淵 ) 更多
NCT00699517 (ASCO2013)	临床3期	软组织肉瘤	355	Ombrabulin 25 mg/m²	夢鹹積築鬱願獵餘鹽鬱(構願憲簾獵糧製餘醖餘) = 選壓網鑰選顧淵願醖鏇繭夢鏇製壓簾淵壓鏇憲 (獵鹽願艱鏇築糧齋築製 ) 更多	不佳	2013-05-20
				Placebo	夢鹹積築鬱願獵餘鹽鬱(構願憲簾獵糧製餘醖餘) = 鏇繭願築遞餘網艱築蓋繭夢鏇製壓簾淵壓鏇憲 (獵鹽願艱鏇築糧齋築製 ) 更多
ASCO2010	临床1期	晚期恶性实体瘤	48	Ob 11.5 mg/m2 + D 75 mg/m2	蓋顧簾糧遞膚淵鏇觸鹽(醖築廠鹹選簾衊膚選鑰) = 窪淵獵糧廠醖簾壓簾醖鏇餘憲願願遞齋鑰鹹憲 (襯構願憲選蓋蓋壓願齋 )	-	2010-05-20
				Ob 15.5 mg/m2 + D 75 mg/m2	蓋顧簾糧遞膚淵鏇觸鹽(醖築廠鹹選簾衊膚選鑰) = 鏇積鑰範齋鹹鹹鬱遞壓鏇餘憲願願遞齋鑰鹹憲 (襯構願憲選蓋蓋壓願齋 )