公开(公告)号：US20070297980A1

公开(公告)日：2007-12-27

申请号：US10594136

申请日：2005-03-28

申请人： Qian Xie ,  David Wenkert ,  Yuchai Shen ,  George Vande Woude ,  Ricky Hay

发明人： Qian Xie ,  David Wenkert ,  Yuchai Shen ,  George Vande Woude ,  Ricky Hay

IPC分类号： A61K31/395 ,  A61K31/397 ,  A61K51/04 ,  A61P35/00 ,  A61P35/04 ,  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： 阻断uPA-纤溶酶网络并抑制成胶质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已知的与hsp90结合的能力不一致，表明在肿瘤发展中存在HGF / SF介导的事件的新靶标。 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了单独或与常规手术，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。

公开(公告)号：US20070207992A1

公开(公告)日：2007-09-06

申请号：US11708226

申请日：2007-02-20

申请人： David Wenkert ,  Leslie Kuhn ,  Erica Scheller ,  Michael Kron ,  Yuehai Shen

发明人： David Wenkert ,  Leslie Kuhn ,  Erica Scheller ,  Michael Kron ,  Yuehai Shen

IPC分类号： A61K31/397 ,  C07D403/02

CPC分类号： C07D225/06

摘要： The present invention relates to novel geldanamycin derivatives which have antitumor and antiparasitic properties. The geldanamycin derivatives disclosed herein have antitumor properties in humans due to their interaction with human heat shock protein 90 (hsp90). The human parasites Plasmodium falciparum, Trypanosoma Cruzi, and Leishmania donovani are lethally susceptible to exposure to geldanamycin via complexation of geldanamycin with their homologs (Pfhsp90, hsp83, and hsp90, respectively) of the human hsp90. The geldanamycin derivatives disclosed herein also interact with these parasitic hsp90 homologs so as to have antiparasitic properties.

摘要翻译： 本发明涉及具有抗肿瘤和抗寄生虫性质的新型格尔德霉素衍生物。 本文公开的格尔德霉素衍生物由于与人类热休克蛋白90（hsp90）的相互作用而在人体中具有抗肿瘤特性。 人类寄生虫恶性疟原虫，克氏锥虫和杜氏利什曼原虫通过与人类hsp90的同源物（分别为Pfhsp90，hsp83和hsp90）的复合而容易接触格尔德霉素。 本文公开的格尔德霉素衍生物还与这些寄生的hsp90同源物相互作用以具有抗寄生虫性质。