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    Methods and compositions for degradation and/or inhibition of HER-family tyrosine kinases
    1.
    发明授权
    Methods and compositions for degradation and/or inhibition of HER-family tyrosine kinases 有权
    用于降解和/或抑制HER-家族酪氨酸激酶的方法和组合物

    公开(公告)号：US07238682B1

    公开(公告)日：2007-07-03

    申请号：US09937192

    申请日：2000-04-07

    申请人： Neal Rosen ,  Scott D. Kuduk ,  Samuel J. Danishefsky ,  Furzhong F. Zheng ,  Laura Sepp-Lorenzino ,  Ouatek Ouerfelli

    发明人： Neal Rosen ,  Scott D. Kuduk ,  Samuel J. Danishefsky ,  Furzhong F. Zheng ,  Laura Sepp-Lorenzino ,  Ouatek Ouerfelli

    IPC分类号： C07D403/02 ,  A61K31/395 ,  A61P35/00

    CPC分类号： C07D403/12

    摘要： Bifunctional molecules comprising two hsp-binding moieties which bind to hsp90 in the pocket to which ansamycin antibiotics bind connected via a linker are effective for inducing the degradation and/or inhibition of HER-family tyrosine kinases. For example, a compound of two geldanamycin moities joined by a four-carbon linker provides selective degradation of HER-family tyrosine kinases, without substantially affecting other kinases. These compounds can be used for treatment of HER-positive cancers with reduced toxicity, since these compounds potently kill cancer cells but affect fewer proteins than geldanamycin.

    摘要翻译： 包含两个hsp结合部分的双功能分子对于诱导HER​​-家族酪氨酸激酶的降解和/或抑制是有效的，所述两个hsp结合部分与口服中与安莎霉素抗生素通过接头连接的hsp90结合。 例如，通过四碳连接物连接的两个格尔德霉素部分的化合物提供HER-家族酪氨酸激酶的选择性降解，而基本上不影响其它激酶。 这些化合物可用于治疗具有降低毒性的HER阳性癌症，因为这些化合物有效杀死癌细胞，但影响比格尔德霉素少的蛋白质。

    Methods and compositions for degradation and/or inhibition of HER-family tyrosine kinases
    2.
    发明授权
    Methods and compositions for degradation and/or inhibition of HER-family tyrosine kinases 失效
    用于降解和/或抑制HER-家族酪氨酸激酶的方法和组合物

    公开(公告)号：US07271160B2

    公开(公告)日：2007-09-18

    申请号：US09960665

    申请日：2001-09-21

    申请人： Neal Rosen ,  Scott D. Kuduk ,  Samuel J. Danishefsky ,  Furzhong F. Zheng ,  Laura Sepp-Lorenzino ,  Ouatek Ouerfelli

    发明人： Neal Rosen ,  Scott D. Kuduk ,  Samuel J. Danishefsky ,  Furzhong F. Zheng ,  Laura Sepp-Lorenzino ,  Ouatek Ouerfelli

    IPC分类号： C07D403/02 ,  A61K31/395 ,  A61P35/00

    CPC分类号： C07D225/06 ,  A61K47/55

    摘要： Bifunctional molecules comprising two hsp-binding moieties which bind to hsp90 in the pocket to which ansamycin antibiotics bind connected via a linker are effective for inducing the degradation and/or inhibition of HER-family tyrosine kinases. For example, a compound of two geldanamycin moities joined by a four-carbon linker provides selective degradation of HER-family tyrosine kinases, without substantially affecting other kinases. These compounds can be used for treatment of HER-positive cancers with reduced toxicity, since these compounds potently kill cancer cells but affect fewer proteins than geldanamycin.

    摘要翻译： 包含两个hsp结合部分的双功能分子对于诱导HER​​-家族酪氨酸激酶的降解和/或抑制是有效的，所述hsp结合部分与口服中与安莎霉素抗生素通过接头连接的hsp90结合。 例如，通过四碳连接物连接的两个格尔德霉素系的化合物提供HER-家族酪氨酸激酶的选择性降解，而基本上不影响其它激酶。 这些化合物可用于治疗具有降低毒性的HER阳性癌症，因为这些化合物有效杀死癌细胞，但影响比格尔德霉素少的蛋白质。

    Methods and compositions for destruction of selected proteins
    4.
    发明授权
    Methods and compositions for destruction of selected proteins 失效
    用于破坏所选蛋白质的方法和组合物

    公开(公告)号：US06670348B1

    公开(公告)日：2003-12-30

    申请号：US09403434

    申请日：1999-10-20

    申请人： Neal Rosen ,  Samuel Danishefsky ,  Ouathek Ouerfelli ,  Scott D. Kuduk ,  Laura Sepp-Lorenzino

    发明人： Neal Rosen ,  Samuel Danishefsky ,  Ouathek Ouerfelli ,  Scott D. Kuduk ,  Laura Sepp-Lorenzino

    IPC分类号： A61K3131

    CPC分类号： C07D225/06 ,  A61K47/554 ,  C07J17/00 ,  C07J43/00

    摘要： Compounds having an ansamycin anitibiotic, or other moiety which binds to hsp90, coupled to a targeting moiety which binds specifically to a protein, receptor or marker can provide effective targeted delivery of the ansamycin antibiotic leading to the degradation of proteins and death of the targeted cells. These compositions may have different specificity than the ansamycin alone, allowing for a more specific targeting of the therapy, and can be effective in instances where the ansamycin alone has no effect. Thus, these compounds provide an entirely new class of targeted chemotherapy agents with application, depending on the nature of the targeting moiety, to treatment of a variety of different forms of cancer. Such agents can further be used to promote selective degradation of proteins associated with the pathogenesis of others diseases, including antigens associated with autoimmune disorders and pathogenic proteins associated with Alzheimer's disease. Exemplary targeting moieties which may be employed in compounds of the invention include testosterone, estradiol, tamoxifen and wortmannin.

    摘要翻译： 具有安莎霉素无抗生素或与hsp90结合的其它部分的化合物偶联到特异性结合蛋白质，受体或标记的靶向部分可以提供安莎霉素抗生素的有效靶向递送，导致蛋白质的降解和靶细胞的死亡 。 这些组合物可以具有与单独的安莎霉素不同的特异性，允许治疗更具体的靶向，并且在单独使用安沙霉素没有作用的情况下可以是有效的。 因此，根据靶向部分的性质，这些化合物提供了一类全新的靶向化学疗法，可用于治疗多种不同形式的癌症。 此类试剂可进一步用于促进与其他疾病发病相关的蛋白质的选择性降解，所述疾病包括与自身免疫疾病相关的抗原和与阿尔茨海默病有关的病原性蛋白质。 可用于本发明化合物的示例性靶向部分包括睾酮，雌二醇，他莫昔芬和渥曼青霉素。

    Small molecule compositions for binding to hsp90
    9.
    发明授权
    Small molecule compositions for binding to hsp90 有权
    用于结合hsp90的小分子组合物

    公开(公告)号：US07439359B2

    公开(公告)日：2008-10-21

    申请号：US10415868

    申请日：2001-11-01

    申请人： Gabriela Chiosis ,  Neal Rosen

    发明人： Gabriela Chiosis ,  Neal Rosen

    IPC分类号： C07D473/40 ,  C07D473/30 ,  C07D473/34 ,  A61K31/52 ,  A61K31/522 ,  A61P35/00

    CPC分类号： C07D473/00 ,  A61K31/52 ,  C07D209/36 ,  C07D473/34 ,  C07D473/40

    摘要： Structural differences in binding pockets of members of the HSP90 family can be exploited to achieve differential degradation of kinases and other signaling proteins through the use of designed small molecules which interact with the N-terminal binding pocket with an affinity which is greater than ADP and different from the ansamycin antibiotics for at least one species of the HSP90 family. Moreover, these small molecules can be designed to be soluble in aqueous media, thus providing a further advantage over the use of ansamycin antibiotics. Pharmaceutical compositions can be formulated containing a pharmaceutically acceptable carrier and a molecule that includes a binding moiety which binds to the N-terminal pocket of at least one member of the HSP90 family of proteins. Such binding moieties were found to have antiproliferative activity against tumor cells which are dependent on proteins requiring chaperones of the HSP90 family for their function. Different chemical species have different activity, however, allowing the selection of, for example Her2 degradation without degradation of Raf kinase. Thus, the binding moieties possess an inherent targeting capacity. In addition, the small molecules can be linked to targeting moieties to provide targeting of the activity to specific classes of cells. Thus, the invention further provides a method for treatment of diseases, including cancers, by administration of these compositions. Dimeric forms of the binding moieties may also be employed.

    摘要翻译： 可以利用HSP90家族成员的结合口袋的结构差异，通过使用与N末端结合口袋相互作用的设计的小分子来实现激酶和其他信号传导蛋白质的差异降解，其亲和力大于ADP和不同 对于至少一种HSP90家族的安莎霉素抗生素。 此外，这些小分子可以被设计成可溶于含水介质，因此比使用安莎霉素抗生素提供了进一步的优点。 药物组合物可以配制成含有药学上可接受的载体和分子，该分子包括与蛋白质的HSP90家族的至少一个成员的N-末端口袋结合的结合部分。 发现这样的结合部分具有抗肿瘤细胞的抗增殖活性，其依赖于需要HSP90家族伴侣的功能的蛋白质。 不同的化学物质具有不同的活性，然而，允许选择例如Her2降解而不降解Raf激酶。 因此，结合部分具有固有的靶向能力。 此外，小分子可以连接到靶向部分，以提供对特定细胞类别的活性的靶向。 因此，本发明还提供了通过施用这些组合物来治疗疾病，包括癌症的方法。 还可以使用结合部分的二聚体形式。