The purpose of this study is to determine the antitumor activity of PHA-739358 as single agent IV infusion in adult patients with Multiple Myeloma who have a history of at least 2 previous lines of treatment for the disease.

开始日期2008-10-01

申办/合作机构

Nerviano Medical Sciences S.r.l

EUCTR2007-005425-30-FR

/ Not yet recruiting临床2期

An Exploratory Phase II Study of PHA-739358 in Patients with Multiple Myeloma Harbouring the t (4;14) translocation with or without FGFR3 Expression

开始日期2008-04-17

申办/合作机构

Nerviano Medical Sciences Group SRL

100 项与达那色替相关的临床结果

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100 项与达那色替相关的转化医学

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100 项与达那色替相关的专利（医药）

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191

项与达那色替相关的文献（医药）

2024-12-01·Molecular Diversity

Ligand-based pharmacophore modeling and machine learning for the discovery of potent aurora A kinase inhibitory leads of novel chemotypes

Article

作者: Banat, Rajaa ; Daoud, Safa ; Taha, Mutasem Omar

Aurora-A (AURKA) is serine/threonine protein kinase involved in the regulation of numerous processes of cell division. Numerous studies have demonstrated strong association between AURKA and cancer. AURKA is overexpressed in many cancers, such as colon, breast and prostate cancers. Consequently, AURKA has emerged as promising target for therapeutic intervention in cancer management. Herein, we describe a computational workflow for the discovery of novel anti-AURKA inhibitory leads starting with ligand-based assessment of the pharmacophoric space of six diverse sets of inhibitors. Subsequently, machine learning/QSAR modeling was coupled with genetic function algorithm to search for the best possible combination of machine learner, ligand-based pharmacophore(s) and molecular descriptors capable of explaining variation in anti-AURKA bioactivities within a collected list of inhibitors. Two learners succeeded in achieving acceptable structure/activity correlations, namely, random forests and extreme gradient boosting (XGBoost). Three pharmacophores emerged in the successful ML models. These were then used as 3D search queries to mine the National Cancer Institute database for novel anti-AURKA leads. Top-ranking 38 hits were assessed in vitro for their anti-AURKA bioactivities. Among them, three compounds exhibited promising dose-response curves, demonstrating experimental IC₅₀ values ranging from sub-micromolar to low micromolar values. Remarkably, two of these compounds are of novel chemotypes.

2024-11-01·Journal of Molecular Liquids

Identification of Aurora A kinase allosteric inhibitors: A comprehensive virtual screening through fingerprint-based similarity search, molecular docking, machine learning and molecular dynamics simulation

作者: Sardarsinh Suryawanshi, Vikramsinh ; Chunarkar Patil, Pritee ; Pravin Pawar, Surbhi ; Abdelghani, Heba Taha M. ; Sudhir Kolpe, Mahima ; Bhowmick, Shovonlal

The Aurora A kinase (AAK) protein controls spindle assembly and promotes cell divisions in various diseases including cancer.In the present study, allosteric inhibition of AAK protein through different advanced computational screening approaches is employed to target AAK's allosteric inhibition-modulation.Precisely, extensive computational techniques including allosteric binding sites recognition of AAK protein, fingerprint-based similarity search, multi-step mol. docking through AutoDock Vina and PLANTS, and a 100 ns mol. dynamics (MD) simulations studies were carried out followed by the calculation of binding free energy with MM-GBSA based approaches, has been employed for identification of potential allosteric inhibitors-modulators of AAK protein.The study outcome highlighted that all three identified small mol. chem. entities exhibit strong binding interaction affinity in both the docking analyses at the allosteric domain of AAK protein and also greater interaction stability in comparison to the considered standard compoundIn addition, all identified three screened hits also show acceptable pharmacokinetics and medicinal chem. properties, which certainly dictates their potentiality for becoming good drug-like compounds for inhibiting-modulating the activity of AAK protein binds with similar amino acids of the allosteric domain of AAK protein with selected three compoundsAll the selected mols. were found to show an acceptable ADMET profile.Moreover, the MM-GBSA-based binding energy was found to be in the range of -8 to -35 Kcal/mol, which showed a strong association between proposed mols. and AAK protein.Comprehensive computational approach shows that the selected proposed three inhibitors of AAK protein are the best candidates as potential inhibitors.

2024-08-01·Cancer Letters

Drug-induced senescence by aurora kinase inhibitors attenuates innate immune response of macrophages on gastric cancer organoids

Article

作者: Cheong, Io Hong ; Kozlakidis, Zisis ; Du, Yutong ; Yan, Ranlin ; Zang, Lu ; Li, Chen ; Zhu, Zhenggang ; Kwan, Wingyan ; Yang, Ruixin ; Yu, Yingyan

Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with aggressiveness and poor prognosis. It is of great significance to find sensitive drugs for DGC. In the current study, a total of 20 patient-derived organoids (PDOs) were analyzed for screening the therapeutic efficacy of small molecule kinases inhibitors on gastric cancers, especially the therapeutic difference between intestinal-type gastric cancer (IGCs) and DGCs. The IGCs are sensitive to multiple kinases inhibitors, while DGCs are resistant to most of these kinases inhibitors. It was found that DGCs showed drug-induced senescent phenotype after treatment by aurora kinases inhibitors (AURKi) Barasertib-HQPA and Danusertib. The cell diameter of cancer cells are increased with stronger staining of senescence-associated β-galactosidase (SA-β-GAL), and characteristic appearance of multinucleated giant cells. The senescent cancer cells secrete large amounts of chemokine MCP-1/CCL2, which recruit and induce macrophage to M2-type polarization in PDOs of DGC (DPDOs)-macrophage co-culture system. The up-regulation of local MCP-1/CCL2 can interact with MCP-1/CCL2 receptor (CCR2) expressed on macrophages and suppress their innate immunity to cancer cells. Overall, the special response of DGC to AURKi suggests that clinicians should select a sequential therapy with senescent cell clearance after AURKi treatment for DGC.

项与达那色替相关的新闻（医药）

2024-07-25

·生物谷

上海交通大学于颖彦教授揭示极光激酶抑制剂诱导的胃癌类器官衰老可削弱巨噬细胞的天然免疫反应

2024年7月，于颖彦教授在《Cancer Letters》【IF9.1，Q1】杂志在线发表题名为“Drug-induced senescence by aurora kinase inhibitors attenuates innate immune response of macrophages on gastric cancer organoids.”——极光激酶抑制剂诱导的胃癌类器官衰老可削弱巨噬细胞的天然免疫反应的研究论文。瑞金医院普外科/上海消化外科研究所于颖彦教授、WHO 国际癌症研究机构Zisis Kozlakidis 教授为论文的共同通讯作者；瑞金医院普外科/上海消化外科研究所杨蕊馨博士研究生、关颖欣博士研究生为论文的共同第一作者。 doi：10.1016/j.canlet.2024.217106. 中文摘要弥漫型胃癌（DGC）以浸润性强、容易转移、预后较差而著称。研发靶向弥漫型胃癌的药物具有重要意义。该研究中，团队利用患者来源类器官（PDO）对一组小分子激酶抑制剂进行筛选，尤其关注不同亚型胃癌的敏感性差异。发现肠型胃癌（IGC）对多种激酶抑制剂敏感，而DGC显示耐药，并在极光激酶抑制剂（AURKi）巴拉塞替（Barasertib）和达努塞替（Danusertib）治疗后出现药物性肿瘤细胞衰老改变，表现为细胞体积增大，出现多核瘤巨细胞，并呈现衰老相关β-半乳糖苷酶（SA-β-GAL）染色强阳性。肿瘤细胞分泌大量的炎症趋化因子MCP-1/CCL2，诱导单核巨噬细胞聚集并发生M2极化，导致原本来杀伤肿瘤的机体天然免疫巨噬细胞杀伤力减弱。这种新型免疫抑制机制的发现提示，对于弥漫型胃癌可采用AURKi + 清除衰老肿瘤细胞的序贯治疗。 Abstract Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with aggressiveness andpoor prognosis. It is of great significance to find sensitive drugs for DGC. In the current study, a total of 20 patient-derived organoids(PDOs) were analyzed for screening the therapeutic efficacy of small molecule kinases inhibitors ongastric cancers, especially the therapeutic difference betweenintestinal-type gastric cancer (IGCs) and DGCs. The IGCs are sensitive to multiple kinases inhibitors, while DGCs are resistantto most of these kinases inhibitors. It was found that DGCs showed drug-induced senescent phenotype after treatment by aurora kinases inhibitors(AURKi) Barasertib-HQPA and Danusertib. The cell diameter of cancer cells are increased with stronger staining of senescence-associated β-galactosidase (SA-β-GAL), and characteristic appearance of multinucleated giant cells. The senescent cancer cells secrete large amounts of chemokine MCP-1/CCL2, which recruitand inducemacrophage to M2-type polarizationin PDOs of DGC (DPDOs)-macrophage co-culturesystem. The up-regulation of local MCP-1/CCL2 can interact with MCP-1/CCL2 receptor (CCR2)expressed on macrophages and suppress theirinnate immunity tocancer cells.Overall, the special response of DGC to AURKisuggests that clinicians should select a sequential therapy withsenescent cell clearanceafter AURKi treatment for DGC. 该研究首先探讨了不同亚型胃癌PDO对小分子激酶抑制剂的敏感性差异。采用96孔板对2例肠型胃癌PDO （IPDO）和4例弥漫型胃癌PDO（DPDO）筛选了11种激酶抑制剂的药物敏感性。其中IPDO对多种激酶抑制剂均敏感，而DPDO对激酶抑制剂的敏感性均较差。4例DPDO的表型均显示细胞之间黏附性较差，细胞分布杂乱无极性。采用AURKi Barasertib和Danusertib处理48小时，肿瘤细胞直径显著变大，但并没有发生明显的细胞裂解坏死，而是出现瘤巨细胞变化，高度提示为细胞衰老，遂进行了SA-β-GAL染色，证实AURKi诱导的细胞SA-β-GAL染色显著增强。在Giemsa染色下，AURKi处理组的DPDO肿瘤细胞体积显著增大，出现多核及巨核瘤巨细胞衰老表型特征。作者遂收集了经SA-β-GAL染色证实的8例早期传代活力良好类器官的培养上清和6例衰老类器官的培养上清，检测了12种炎症相关因子的含量变化。随着类器官传代次数增加，培养上清中单核巨噬细胞趋化因子MCP-1/CCL2的含量升高程度最为明显。采用AURKi处理的DPDO培养上清液也检查到高含量的MCP-1/CCL2。经过对开源数据库胃癌单细胞测序数据集（GSE163558）的细胞分群与炎症相关因子表达水平分析，在7个上皮来源细胞亚群中，C3亚群高表达衰老相关基因CDKN2A和CDKN2B，同时，MCP-1/CCL2阳性表达细胞比例最高。利用GSEA通路富集分析发现，高表达MCP-1/CCL2的C3亚群的基因集主要富集在ROS通路、蛋白质分泌通路、EMT通路和炎症反应通路等等。以集落刺激因子1受体CSF1R作为巨噬细胞标志基因，对巨噬细胞亚群进行分析发现，其M2极化巨噬细胞的MCP-1/CCL2阳性表达细胞比例最高。GSEA通路富集分析显示，M2型巨噬细胞上调的基因集主要富集在TNFα信号通路、EMT通路、促血管生成通路及蛋白质分泌通路等等。乳酸脱氢酶（LDH）释放量可以反映细胞膜的完整性，研究人员测定了DPDO-巨噬细胞共培养体系内添加rhMCP-1处理对LDH释放的影响。与对照组相比，rhMCP-1处理组的LDH释放量显著降低，表明微环境内MCP-1/CCL2的增加致使巨噬细胞对肿瘤的吞噬杀伤作用减弱。对肿瘤细胞涂片进行Giemsa染色，可见未经rhMCP-1处理的肿瘤细胞裂解增加，而rhMCP-1处理组的肿瘤细胞形态保留完整，细胞体积增大。采用siRNA干扰巨噬细胞表面的CCR2受体表达，则巨噬细胞受MCP-1/CCL2趋化因子影响减少，细胞迁移能力明显减弱。在抗癌药物筛选领域，诱发细胞衰老从而阻滞肿瘤生长是候选策略之一。然而，“老而不死”肿瘤细胞的生物学作用尚有待深入研究。近年来细胞衰老机制研究有了长足发展，衰老细胞可以通过自分泌或者旁分泌产生大量细胞因子与炎症因子,构成衰老相关分泌表型（SASP），但SASP对胃癌细胞的影响尚不清楚。该研究将类器官实验研究与外部单细胞测序数据集分析相结合，鉴定到衰老的肿瘤上皮细胞可以产生大量的MCP-1/CCL2炎症趋化因子，趋化单核巨噬细胞聚集到肿瘤周围，诱发单核巨噬细胞向M2极化，从而削弱了单核细胞吞噬杀伤肿瘤的能力。该研究与最近几项在其它类型肿瘤的研究结果不谋而合。近来已有研究显示，肿瘤细胞衰老是一种不容忽视的现象，此类细胞有可能成为肿瘤复发与转移的根源，应当积极探索靶向衰老肿瘤细胞的干预策略。针对弥漫型胃癌的这种药物反应特性，可以考虑AURKi+衰老细胞靶向清除的序贯疗法作为一种新型治疗策略。作者介绍于颖彦主任医师，教授，博士研究生导师，上海交通大学医学院附属瑞金医院普外科/上海消化外科研究所；研究方向：胃癌的基础与转化研究。杨蕊馨博士研究生，上海交通大学医学院附属瑞金医院普外科/上海消化外科研究所；研究方向：胃癌发病机制及靶向治疗。关颖欣博士研究生，上海交通大学医学院附属瑞金医院普外科/上海消化外科研究所；研究方向：胃癌发病机制及靶向治疗。【扫描二维码可下载原文】 Drug-induced senescence by aurora kinase inhibitors attenuates innate immune response of macrophages on gastric cancer organoids.pdf

临床研究

100 项与达那色替相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11778

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
费城染色体阳性慢性粒细胞白血病	临床2期	-	Nerviano Medical Sciences S.r.l	-
神经母细胞瘤	临床前	意大利	Nerviano Medical Sciences Group SRL	2017-03-26
小细胞肺癌	临床前	意大利	Nerviano Medical Sciences Group SRL	2017-02-26
多发性骨髓瘤	临床前	美国	Nerviano Medical Sciences S.r.l	2008-10-01
多发性骨髓瘤	临床前	法国	Nerviano Medical Sciences S.r.l	2008-10-01
去势抵抗性前列腺癌	临床前	荷兰	Nerviano Medical Sciences Group SRL	2008-02-07
转移性去势抵抗性前列腺癌	临床前	意大利	Nerviano Medical Sciences S.r.l	2007-09-01

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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


EUCTR2006-003772-35-BE (not available, ASCO2013)	临床2期	转移性非小细胞肺癌	56	Danusertib	(糧艱築鑰壓鹹餘蓋憲顧) = 鹽衊鹽範醖築淵襯廠襯鑰壓鬱積淵醖淵齋壓鏇 (遞淵範齋鹹遞範繭憲選 ) 更多	-	2013-05-20
ASCO2011	临床2期	转移性去势抵抗性前列腺癌二线	43	Danusertib 330 mg/m2 over 6h IV	(獵艱網簾築壓廠繭糧觸) = 夢糧廠願蓋蓋網淵鹽構鬱蓋衊積廠鹹範範遞蓋 (壓淵膚廠壓範蓋顧製願, 10.86 ~ 15.14)	-	2011-05-20
ASCO2011	临床2期	转移性去势抵抗性前列腺癌二线	43	Danusertib 500 mg/m2 over 24h IV	(獵艱網簾築壓廠繭糧觸) = 顧鑰窪鹹憲觸鏇構觸衊鬱蓋衊積廠鹹範範遞蓋 (壓淵膚廠壓範蓋顧製願, 10.71 ~ 17.29)	-	2011-05-20
ASCO2008	临床1期	HR阳性/HER2低表达实体瘤	40	PHA-739358 without G-CSF	(簾鏇選繭鏇餘遞鹹淵觸) = 製簾壓膚鏇艱築糧選廠築顧壓鹽觸壓壓鹽艱鹹 (壓齋簾繭範廠衊網築構 ) 更多	-	2008-05-20