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    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 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
    5.
    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。

    Small molecule compositions for binding to hsp90
    7.
    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。

    Biomarkers for cancer treatment
    9.
    发明授权
    Biomarkers for cancer treatment 有权
    用于癌症治疗的生物标志物

    公开(公告)号：US07812143B2

    公开(公告)日：2010-10-12

    申请号：US11732362

    申请日：2007-04-02

    申请人： Christine Pratilas ,  Neal Rosen

    发明人： Christine Pratilas ,  Neal Rosen

    IPC分类号： C07H21/04

    CPC分类号： C12Q1/6886 ,  C12Q2600/106 ,  C12Q2600/136 ,  C12Q2600/158

    摘要： The present invention provides identification of a thirty-five gene set that predicts the anticancer activity of inhibitors of the RAF/MEK/MAPK pathway, methods of qualifying cancer status in a subject, methods of identifying an anti-tumor response in a subject, methods of monitoring the efficacy of a therapeutic drug in a subject, and methods of identifying an agent useful in the treatment of a cancer based on expression of the thirty-five gene set.

    摘要翻译： 本发明提供了预测RAF / MEK / MAPK途径的抑制剂的抗癌活​​性的三十五种基因组的鉴定，在受试者中鉴定癌症状态的方法，鉴定受试者中抗肿瘤反应的方法，方法 监测治疗药物在受试者中的功效的方法，以及基于三十五种基因组表达鉴定可用于治疗癌症的药剂的方法。

    Methods and compositions for the detection of drug resistant BRAF isoforms
    10.
    发明授权
    Methods and compositions for the detection of drug resistant BRAF isoforms 有权
    用于检测耐药BRAF同种型的方法和组合物

    公开(公告)号：US09481910B2

    公开(公告)日：2016-11-01

    申请号：US13480050

    申请日：2012-05-24

    申请人： Neal Rosen ,  Poulikos Poulikakos ,  David Solit

    发明人： Neal Rosen ,  Poulikos Poulikakos ,  David Solit

    IPC分类号： C12Q1/68

    CPC分类号： C12Q1/6886 ,  C12Q2600/156 ,  C12Q2600/158

    摘要： The present invention provides methods and compositions for the detection of novel BRAF splice variants that mediate resistance to BRAF and/or pan-RAF inhibitors. In particular, the invention provides PCR primer(s) to be used in the disclosed methods of detection. In some embodiments, the compositions and methods of the present invention are used to predict resistance to BRAF and/or pan-RAF inhibitors in a subject suffering from or suspected of having cancer and further provides alternative treatment strategy(ies) for a subject predicted to be resistant to BRAF and/or pan-RAF inhibitors. In a further embodiment, methods and composition for the identification of novel agents useful to overcome resistance to BRAF and/or pan-RAF inhibitors are disclosed. The present invention also provides isolated polynucleotide sequences of novel 5′ BRAF splice variant(s) and proteins produced from such polynucleotide sequences as well as cell line(s) that endogenously or exogenously express the splice variant(s).

    摘要翻译： 本发明提供了用于检测介导对BRAF和/或pan-RAF抑制剂的抗性的新型BRAF剪接变体的方法和组合物。 特别地，本发明提供了用于所公开的检测方法的PCR引物。 在一些实施方案中，本发明的组合物和方法用于预测患有或怀疑患有癌症的受试者对BRAF和/或pan-RAF抑制剂的抗性，并且进一步为预测的患者提供替代治疗策略 耐BRAF和/或泛RAF抑制剂。 在另一个实施方案中，公开了用于鉴定用于克服对BRAF和/或pan-RAF抑制剂的抗性的新型试剂的方法和组合物。 本发明还提供新的5'BRAF剪接变体和由这样的多核苷酸序列产生的蛋白质以及内源性或外源表达剪接变体的细胞系的分离的多核苷酸序列。