A phase II study of intravenous TZT-1027, administered weekly times two, every three weeks, to patients with advanced or metastatic soft tissue sarcomas (STS) with prior exposure to doxorubicin-based chemotherapy

开始日期2004-11-08

申办/合作机构

European Organisation for Research & Treatment of Cancer

NCT00061854 / Completed临床2期

A Phase II Study Of Intravenous TZT-1027, Administered Weekly Times Two, Every Three Weeks, To Patients With Progressive Locally Advanced Or Metastatic Non-Small Cell Lung Cancer (NSCLC) Following Treatment With Platinum-Based Chemotherapy

RATIONALE: Drugs used in chemotherapy such as soblidotin use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: Phase II trial to study the effectiveness of soblidotin in treating patients who have progressive locally advanced or metastatic non-small cell lung cancer.

开始日期2003-04-01

申办/合作机构

Daiichi Sankyo, Inc.

NCT00064220 / Completed临床2期

A Phase II Study of Intravenous TZT-1027, Administered Weekly Times Two, Every Three Weeks, to Patients With Advanced or Metastatic Soft Tissue Sarcomas (STS) With Prior Exposure to Anthracycline-Based Chemotherapy

开始日期2003-04-01

申办/合作机构

Daiichi Sankyo, Inc.

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100 项与 Soblidotin 相关的临床结果

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100 项与 Soblidotin 相关的转化医学

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100 项与 Soblidotin 相关的专利（医药）

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项与 Soblidotin 相关的文献（医药）

2022-07-03·Journal of biomolecular structure & dynamics

Cytotoxicity, in silico predictions and molecular studies for androstane heterocycle compounds revealed potential antitumor agent against lung cancer cells

Article

作者: Shaheen, Sameerah ; Nafie, Mohamed S. ; Kattan, Shahad W. ; Tantawy, Mohamed A. ; Barnawi, Ibrahim O. ; Elmgeed, Gamal A. ; Alelwani, Walla

The IL6/JAK2/STAT3 axis dysregulation and the related downstream pathways are a major contributor to the progression of non-small-cell lung carcinoma (NSCLC) and mainly affect apoptosis. Furthermore, tubulin inhibitors are potential chemotherapeutic agents against NSCLC. In this study, we have provided new molecular insights into the antiproliferative activity of six 3β-acetoxy-5α-androstane heterocycle compounds against NSCLC. The cell line A549, which represents a good model of NSCLC, was used to evaluate the antitumour activity of tested androstane derivatives, and non-cancerous gingival mesenchymal stem cell line (GMSC) were used to assess the specificity and toxicity of the tested compounds. Further on, molecular docking predictions were used to determine the molecular targets for the most promising cytotoxic compound. To assess apoptosis and cell cycle progression in treated A549 cells, flow cytometry was used. RT-qPCR and ELISA analyses were used to gain deep insights into cellular and molecular mechanisms. Results revealed that compound 4 has potential cytotoxicity on A549 cells, with lower IC₅₀ value (27.36 μM). Moreover, in silico, compound 4 showed a good binding affinity to JAK2 and tubulin-colchicine soblidotin molecular targets. This was further confirmed on the molecular level. Compound 4 has also led to apoptosis and increased fragmentation of DNA, and mitochondrial dysfunction. Our findings have provided good evidence that compound 4 may be a dual inhibitor of IL6/JAK2/STAT3 and tubulin formation in lung cancer. These findings support further molecular exploration of this androstane derivative as promising anti-lung cancer agent.Communicated by Ramaswamy H. Sarma.

2021-08-01·Computers in biology and medicine3区 · 工程技术

Unravelling the therapeutic potential of marine drugs as SARS-CoV-2 inhibitors: An insight from essential dynamics and free energy landscape

3区 · 工程技术

Article

作者: Lee, Keun Woo ; Rampogu, Shailima ; Lee, Gihwan ; Kim, Myeong Ok ; Gajula, Rajesh Goud

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic. The virus that causes the disease, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), predominantly infects the respiratory tract, which may lead to pneumonia and death in severe cases. Many marine compounds have been found to have immense medicinal value and have gained approval from the Food and Drug Administration (FDA), and some are being tested in clinical trials. In the current investigation, we redirected a number of marine compounds toward SARS-CoV-2 by targeting the main protease (M^pro, PDB ID: 6Y2F), subjecting them to several advanced computational techniques using co-crystallised ligand as the reference compound. The results of the binding affinity studies showed that two compounds, eribulin mesylate (eri) and soblidotin (sob), displayed higher docking scores than did the reference compound. When these compounds were assessed using molecular dynamics simulation, it was evident that they demonstrated stable binding at the binding pocket of the target protein. The systems demonstrated stable root mean square deviation and radius of gyration values, while occupying the binding pocket during the simulation run. Furthermore, the essential dynamics and free energy landscape exploration revealed that the protein had navigated through a minimal energy basin and demonstrated favourable conformation while binding to the proposed inhibitors. Collectively, our findings suggest that two marine compounds, namely eri and sob, show potential as SARS-CoV-2 main protease inhibitors.

2017-09-01·Peptides3区 · 医学

Structural diversity of marine cyclic peptides and their molecular mechanisms for anticancer, antibacterial, antifungal, and other clinical applications

3区 · 医学

Review

作者: Hong, Soon-Cheol ; Lee, Yeji ; Phat, Chanvorleak

Many cyclic peptides and analogues derived from marine sources are known to possess biological properties, including anticancer, antitumor, antibacterial, antifungal, antiparasitic, anti-inflammation, anti-proliferative, anti-hypertensive, cytotoxic, and antibiotic properties. These compounds demonstrate different activities and modes of action according to their structure such as cyclic oligopeptide, cyclic lipopeptide, cyclic glycopeptide and cyclic depsipeptide. The recent advances in application of the above-mentioned cyclic peptides were reported in dolastatins, soblidotin, didemnin B, aplidine, salinosporamide A, kahalalide F and bryostatin 1 and they are currently in clinical trials. These cyclic peptides are possible novel drugs discovered and developed from marine origin. Literature data concerning the potential properties of marine cyclic peptides were reviewed here, and the structural diversity and biological activities of marine cyclic peptides are discussed in relation to the molecular mechanisms of these marine cyclic peptides.

项与 Soblidotin 相关的新闻（医药）

2022-11-23

·BiG生物创新社

浅谈ADC的毒性和治疗窗口

12月21-22日，上海大咖带队，新秀集结！以创新利刃，破内卷之局最近一篇文章在朋友圈里刷屏，不少朋友都短信来询问我的观点。文章是Zymeworks负责ADC开发的团队总结的，观点很抓眼球但是分析不够全面。在纷繁复杂的信息时代，如何梳理信息，逻辑分析和积累知识，建立自己具有深度和广度的立体解析系统尤为重要。首先，文章的第一个观察总结（也算一个观点）以ADC的毒素载量为衡量的MTD和作为化药的同类化合物基本一致，并没有出现明显的提升。同时要指出，这些毒素作为化疗药物使用，由于其较高的疏水性和较差的溶解性，一般在系统的暴露量也会有个折扣，并未体现其实际的毒性，这也是很多毒素化疗药物使用脂质体来助溶和递送的原因。ADC的毒素端在偶联体稳定性和ADC自身稳定性和脱靶毒性没有优化解决前， ADC携带的毒素脱落的暴露, 白蛋白转移和积累总量和单纯用化药时的MTD应该是类似的。用通俗和简化的例子来解释一下，ADC释放的毒素在系统及器官组织暴露量大概是95%，递送至肿瘤的暴露量约1%；而单纯化药的系统&器官组织暴露量约99%，递送至肿瘤的暴露量约0.1%，于是两者的系统毒性均由其系统暴露量以及毒素的自身特征的综合结果，这也是限制ADC用药量的主因，目前的ADC没有做出差异化，如何设计更好的上限，那就是仁者见仁智者见智了。一些高活毒素例如PBD，calicheamicin等在系统毒性对剂量限制的影响则更为明显。而药效方面，ADC就优胜于化疗药物。某些ADC的在靶递送，也有可能造成额外的毒性，如EGFR, trop2, Folate receptor, Nectin4 等。同时毒素和其代谢物，在特定组织和环境也有产生其特有的毒性，如MMAF, DM4的眼毒性，SN38的肠胃炎症，PBD的光敏毒性。ADC的毒性还和患者状况有关，由于受试患者多数是经过多线治疗，身体状况也是较为脆弱，单纯比较MTD的数值，尤其跨越不同临床设计，患者人群以及给药设计等影响。相比之下化疗的起效剂量和其出现频繁DLT 的MTD剂量较为接近，也就是我们常说的治疗窗口(therapeutic index). 用文章中的TZT-1027例子， TZT-1027单药静脉注射3例患者在3.0 mg/m(2) 剂量呈现主要以 neutropenia为症状的DLT, 随而将2.7mg/m2作为RP2D，需要指出的是该药的2期临床是以D1,D8 两次注射，3周一个周期。~40%的患者需要下调剂量，60% 3-4级副反应，关键是没有一例患者出现缓解。换句话这类化药直接用药MTD基本就在最低起效剂量MED附近甚至低于MED。这个原因导致用于ADC的毒素，除了替康，艾日布林类，其他基本都有在单药化疗失败经历。这里还需要强调一点，小分子用药一般更为频繁，跨临床比较，获得的相对值结论需要谨慎。用替康内化合物举个例子，文中有点偷梁换柱的意思，比如Exatecan才是第一三共的Dxd毒素合理的对比化合物而非几个活性稍弱的替康，或者是前药设计的Irinotecan。在临床试验中，exatecan在0.4mg/m2就出现中性粒细胞减少的DLT。这也是第一三共停止单独化药的研究的原因。从这个值来看，DS-8201和其他几款ADC的MTD是大大优于其同源化合物。同理，我们比较belotecan和SKB264, 此类ADC还是有一定的MTD改善。关于MED一般早期临床很少能覆盖，也不是临床方案的重点，获得理论或预测的MED值一般通过临床前药效模型进行跨种属转化模型预测。临床试验通过一些biomarker, 或者PK数据进行验证，由于入组人数的限制在低剂量探索MED一般不会是设计的重点。毒素化疗药物的治疗窗口一般在1~3之间，而ADC目前的治疗窗口在3~10之间。我们仍然有很多进步的空间去优化下一代ADC, 最重要的是知道从哪里下手。文章中罗列了不少过去失败的方案，细心的读者应该可以总结出一些经验教训。2：文中把MTD和RP2D混为一谈，希望zymeworks自己做临床时没有这么草率。我们比较熟悉的几款ADC，考虑到多次给药可能造成的蓄积，以及ADC组织分布的长尾效应，RP2D都会在爬坡的MTD基础上降低一些。下面用DS-1062展示一下， 10mpk组出现两例DLT，因而在8mpk进行确认，随后MTD设置为该剂量8mpk. 实际推荐RP2D为6mpk. 同样immu-132的MTD 为12mpk, 后期临床推荐剂量为10mpk. Zymeworks这篇文章的漏洞不少,可能造成一些理解的出入。总结一下，这篇文章抛出一个耸人听闻的结论，却没有一个细致和系统的分析，造成业界一片惶然。ADC的毒性主要由payload决定，它的载量和释放决定了毒性和药效的比例。由于绝大部分的毒素都会在系统中释放，目前ADC的毒性处于和化药同类接近的水平。关键的是ADC的肿瘤靶向递送以及适当的旁杀效应，使得几款ADC获得不错的治疗效果。未来还有很大的改进空间，关键是对靶点生物学，药物设计的有效结合。扫码加入BiG生物创新社读者交流群，分享、交流纯粹的行业知识，非诚勿扰！BiGScientific Driven, Making Impact!创新生态丨医药论坛丨行业分析媒体公关丨BiG Webinar联系我们商务：Max 18662346610媒体：Kathy 17621909690

抗体药物偶联物临床2期引进/卖出临床结果临床1期

100 项与 Soblidotin 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D01919	-	-	DB12677

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
转移性软组织肉瘤	临床2期	美国	Daiichi Sankyo, Inc.	2003-04-01
转移性软组织肉瘤	临床2期	波多黎各	Daiichi Sankyo, Inc.	2003-04-01
进行性非小细胞肺癌	临床2期	美国	Daiichi Sankyo, Inc.	2003-04-01
非小细胞肺癌	临床2期	-	Yakult Honsha Co., Ltd.	-
非小细胞肺癌	临床2期	-	ASKA Pharmaceutical Co., Ltd.	-
实体瘤	临床1期	美国	Daiichi Pharmaceutical Co., Ltd.	2003-11-04

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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


NCT00064220 (Pubmed \| Cancer)	临床2期	转移性软组织肉瘤	-	TZT-1027	遞顧鹹衊築膚蓋餘齋醖(鏇遞鬱醖選簾網鑰壓膚) = 積糧繭簾願鑰觸鬱夢膚醖壓鹹範鑰遞築願積憲 (選築糧簾選壓夢鹹糧遞 ) 更多	不佳	2006-12-15