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1. 发明申请

WO2007134328A2 GELDANAMYCINS AND THEIR QUINONE MOIETIES INHIBIT CANCER BY ACTING ON MITOCHONDRIAL VOLTAGE-DEPENDENT ANION CHANNEL (VDAC) PROTEIN 审中-公开
标题翻译：通过采用麻醉电压依赖性阴离子通道（VDAC）蛋白，GELDANAMYCINS及其喹诺酮抑制剂
公开(公告)号：WO2007134328A2
公开(公告)日：2007-11-22
申请号：PCT/US2007/068988
申请日：2007-05-15
申请人： VAN ANDEL RESEARCH INSTITUTE , MICHIGAN STATE UNIVERSITY , XIE, Qian , WENKERT, David , SHEN, Yuchai , VANDE WOUDE, George F. , HAY, Rick , WONDERGEM, Robert
发明人： XIE, Qian , WENKERT, David , SHEN, Yuchai , VANDE WOUDE, George F. , HAY, Rick , WONDERGEM, Robert
IPC分类号： H01L51/00
CPC分类号： C07J41/00 , C07C205/22 , C07C205/37 , C07C233/41 , C07D203/14 , C07D225/06 , C07D403/04 , C07D498/04
摘要： Derivatives of geldanamycin (GA), a benzoquinone ansamycin antibiotic, are in clinical trials as anticancer drugs. While, at nanomolar concentrations, these drugs are known to target HSP90 chaperone activity, second anticancer activity that inhibits HGF/SF-mediated tumor cell invasion at nanomolar concentrations has been found. Disclosed is the identification of the outer membrane mitochondrial voltage-dependent anion channel (VDAC) protein, a component of the permeability transition pore (PTP), as a novel GA binding protein and a demonstration that GA inhibits membrane potential at picomolar levels. Uubiquinone 0 and decyl-ubiquinone, known benzoquinone inhibitors of mitochondrial PTP function like GA, inhibit HGF/SF induced urokinase (uPA) plasmin protease activation and HGF/SF activated membrane currents in whole-cell voltage clamp assays, with GA blocking at picomolar levels. The results disclosed regarding mechanism of action are a major step in harnessing such drugs for use for treating highly invasive cancers like glioblastoma.
摘要翻译：格列尔霉素（GA）的衍生物，苯醌安莎霉素抗生素，在临床试验中作为抗癌药物。而在纳摩尔浓度下，已经发现这些药物靶向HSP90伴侣活性，已经发现抑制HGF / SF介导的肿瘤细胞在纳摩尔浓度下的侵袭的第二抗癌活性。公开了作为新型GA结合蛋白的外膜线粒体电压依赖性阴离子通道（VDAC）蛋白（通透性转换孔（PTP）的组分）的鉴定以及GA在皮摩尔水平抑制膜电位的证明。 Uubiquinone 0和癸基泛醌，线粒体PTP功能的已知苯醌抑制剂如GA，抑制HGF / SF诱导的尿激酶（uPA）纤溶酶蛋白酶激活和HGF / SF活化的膜电流，在全细胞电压钳位测定中，GA阻断皮摩尔水平。披露的关于作用机制的结果是利用这些药物用于治疗高侵袭性癌症如胶质母细胞瘤的主要步骤。

2. 发明申请

WO2005095347A1 GELDANAMYCIN AND DERIVATIVES INHIBIT CANCER INVASION AND IDENTIFY NOVEL TARGETS 审中-公开
标题翻译： GELDANAMYCIN和衍生物禁止癌症入侵和鉴定新目标
公开(公告)号：WO2005095347A1
公开(公告)日：2005-10-13
申请号：PCT/US2005/010351
申请日：2005-03-28
申请人： VAN ANDEL RESEARCH INSTITUTE , XIE, Qian , WENKERT, David , SHEN, Yuchai , VANDE WOUDE, George, F. , HAY, Rick
发明人： XIE, Qian , WENKERT, David , SHEN, Yuchai , VANDE WOUDE, George, F. , HAY, Rick
IPC分类号： C07D225/06
CPC分类号： C07D225/06
摘要： Geldanamycin derivatives that block the uPA-plasmin network and inhibit growth and invasion by glioblastoma cells and other tumors at femtomolar concentrations are potentially highly active anti-cancer drugs. GA and various 17-amino-17-demethoxygelddanamycin derivatives are disclosed that block HGF/SF-mediated Met tyrosine kinase receptor-dependent uPA activation at fM levels. Other ansamycins (macbecins I and II), GA derivatives, and radicicol required concentrations several logs higher (≥nM) to achieve such inhibition. The inhibitory activity of tested compounds was discordant with the known ability of drugs of this class to bind to hsp90, indicating the existence of a novel target(s) for HGF/SF -mediated events in tumor development. Methods of using such compounds to inhibit cancer cell activities and to treat tumors are disclosed. Such treatment with low doses of these highly active compounds provide an option for treating various Met-expressing tumors, in particular invasive brain cancers, either alone or in combination with conventional surgery, chemotherapy, or radiotherapy.
摘要翻译：抑制uPA-纤溶酶网络并抑制胶质母细胞瘤细胞和其他肿瘤在飞生物浓度下的生长和侵袭的格尔德霉素衍生物是潜在的高活性抗癌药物。 GA和各种17-氨基-17-脱甲氧基格丹丹霉素衍生物被公开，以fM水平阻断HGF / SF介导的Met酪氨酸激酶受体依赖性uPA活化。其他ansamycins（macbecins I和II），GA衍生物和radicicol要求的浓度几个日志更高（> = nM）达到这种抑制。测试化合物的抑制活性与本类药物与hsp90结合的已知能力不一致，表明存在HGF / SF介导的肿瘤发展事件的靶标。公开了使用这些化合物抑制癌细胞活性和治疗肿瘤的方法。用低剂量的这些高活性化合物的这种治疗提供单独或与常规手术，化学疗法或放射疗法组合治疗各种Met表达肿瘤，特别是侵袭性脑癌的选择。

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