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    Small-Molecule HSP90 Inhibitors
    12.
    发明申请
    Small-Molecule HSP90 Inhibitors 有权
    小分子HSP90抑制剂

    公开(公告)号：US20110104054A1

    公开(公告)日：2011-05-05

    申请号：US12939807

    申请日：2010-11-04

    申请人： Gabriela Chiosis ,  Huazhong He ,  Laura Llauger-bufi ,  Joungnam Kim ,  Steven M. Larson ,  Peter Smith-Jones

    发明人： Gabriela Chiosis ,  Huazhong He ,  Laura Llauger-bufi ,  Joungnam Kim ,  Steven M. Larson ,  Peter Smith-Jones

    IPC分类号： A61K31/52 ,  C07D473/34 ,  A61P35/00 ,  A61K51/00 ,  A61P43/00 ,  C12N5/02

    CPC分类号： C07D473/34 ,  A61K51/0459 ,  C07D491/056 ,  G01N33/60

    摘要： Hsp90 inhibitors having are provided having the formula: with a 2′,4′,5′-substitution pattern on the right-side aryl moiety. X1 represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO2-alkyl, COO-alkyl, KH2, OH, CN, SO2X5, NO2, NO, C═SR2 NSO2X5, C═OR2, where X5 is F, NH2, alkyl or H, and R2 is alkyl, NH2, NH-alkyl or O-alkyl, C1 to C6 alkyl or alkoxy; or wherein X1 has the formula -0-(CH2)n-0-, wherein n is an integer from O to 2, preferably 1 or 2, and one of the oxygens is bonded at the 5′-position and the other at the 4′-position of the aryl ring. The compounds are useful in cancer therapy and as radioimaging ligands.

    摘要翻译： 提供具有下式的Hsp90抑制剂：右侧芳基部分具有2'，4'，5'-取代模式。 X1表示在芳基的4'和5'位置上可以相同或不同的两个取代基，其中X 1选自卤素，烷基，烷氧基，卤代烷氧基，羟基烷基，吡咯基，任选取代的芳氧基，烷基氨基 ，二烷基氨基，氨基甲酰基，酰氨基，烷基酰氨基二烷基酰氨基，酰基氨基，烷基磺酰氨基，三卤甲氧基，三卤代烷基，硫代烷基，SO2-烷基，COO-烷基，KH 2，OH，CN，SO 2 X 5，NO 2，NO，C≡SR2 NSO 2 X 5，C = OR 2，其中 X5是F，NH2，烷基或H，R2是烷基，NH2，NH-烷基或O-烷基，C1-C6烷基或烷氧基; 或其中X 1具有式-O-（CH 2）n -O-，其中n是0至2的整数，优选1或2，并且其中一个氧键在5'-位上而另一个在 芳基环的4'-位。 该化合物可用于癌症治疗和放射成像配体。

    Small-molecule Hsp90 inhibitors
    13.
    发明授权
    Small-molecule Hsp90 inhibitors 有权
    小分子Hsp90抑制剂

    公开(公告)号：US09403828B2

    公开(公告)日：2016-08-02

    申请号：US13176903

    申请日：2011-07-06

    申请人： Gabriela Chiosis

    发明人： Gabriela Chiosis

    IPC分类号： C07D473/34

    CPC分类号： C07D473/34 ,  C07D519/00

    摘要： Purine scaffold Hsp90 inhibitors are useful in therapeutic applications and as radioimaging ligands.

    摘要翻译： 嘌呤支架Hsp90抑制剂可用于治疗应用和放射成像配体。

    Small-molecule Hsp90 inhibitors
    14.
    发明授权
    Small-molecule Hsp90 inhibitors 有权
    小分子Hsp90抑制剂

    公开(公告)号：US07834181B2

    公开(公告)日：2010-11-16

    申请号：US11814506

    申请日：2006-02-01

    申请人： Gabriela Chiosis ,  Huazhong He ,  Laura Llauger-Bufi ,  Joungnam Kim ,  Steve M. Larson ,  Peter Smith-Jones

    发明人： Gabriela Chiosis ,  Huazhong He ,  Laura Llauger-Bufi ,  Joungnam Kim ,  Steve M. Larson ,  Peter Smith-Jones

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

    CPC分类号： C07D473/34 ,  A61K51/0459 ,  C07D491/056 ,  G01N33/60

    摘要： Hsp90 inhibitors are provided having the formula: with a 2′,4′,5′-substitution pattern on the right-side aryl moiety. X1 represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO2−alkyl, COO-alkyl, KH2, OH, CN, SO2X5, NO2, NO, C═SR2 NSO2X5, C═OR2, where X5 is F, NH2, alkyl or H, and R2 is alkyl, NH2, NH-alkyl or O-alkyl, C1 to C6 alkyl or alkoxy; or wherein X1 has the formula —O—(CH2)n—O—, wherein n is an integer from 0 to 2, preferably 1 or 2, and one of the oxygen is bonded at the 5′-position and the other at the 4′-position of the aryl ring. The compounds are useful in cancer therapy and as radioimaging ligands.

    摘要翻译： 提供具有下式的Hsp90抑制剂：右侧芳基部分具有2'，4'，5'-取代模式。 X1表示在芳基的4'和5'位置上可以相同或不同的两个取代基，其中X 1选自卤素，烷基，烷氧基，卤代烷氧基，羟基烷基，吡咯基，任选取代的芳氧基，烷基氨基 ，二烷基氨基，氨基甲酰基，酰氨基，烷基酰氨基二烷基酰氨基，酰基氨基，烷基磺酰氨基，三卤甲氧基，三卤代烷基，硫代烷基，SO2-烷基，COO-烷基，KH 2，OH，CN，SO 2 X 5，NO 2，NO，C≡SR2 NSO 2 X 5，C = OR 2，其中 X5是F，NH2，烷基或H，R2是烷基，NH2，NH-烷基或O-烷基，C1-C6烷基或烷氧基; 或其中X 1具有式-O-（CH 2）n -O-的化合物，其中n为0至2的整数，优选1或2，并且一个氧键在5'位置而另一个在 芳基环的4'-位。 该化合物可用于癌症治疗和放射成像配体。

    Small molecule compositions for binding to hsp90
    15.
    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。

    Assays for detection of bioactive compounds that interact with heat shock protein 90
    17.
    发明申请
    Assays for detection of bioactive compounds that interact with heat shock protein 90 审中-公开
    用于检测与热休克蛋白90相互作用的生物活性化合物的测定

    公开(公告)号：US20070178537A1

    公开(公告)日：2007-08-02

    申请号：US10595029

    申请日：2004-06-30

    申请人： Gabriela Chiosis ,  Neal Rosen ,  Henri Huezo

    发明人： Gabriela Chiosis ,  Neal Rosen ,  Henri Huezo

    IPC分类号： G01N33/574 ,  C07K16/46

    CPC分类号： G01N33/542 ,  C07D405/12 ,  G01N33/5008 ,  G01N33/5011 ,  G01N33/582 ,  G01N33/68 ,  G01N33/6845 ,  G01N2500/00 ,  G01N2500/02

    摘要： A method for evaluation of molecules to identify those that can act as therapeutic inhibitors of Hsp90 makes use of a fluorescence polarization (FP) assay and a cell based assay, either individually or in combination. The FP assay uses a fluorescently-labeled Hsp90 binding agent and measure the degree of fluorescence polarization relative to the standard. A decrease in the degree of polarization indicates that fluorescently-labeled Hsp90 binding agent has been wholly or partially displaced by a candidate molecule, and identifies the molecule as having activity as an inhibitor of Hsp90. The cell based assay tests for decrease is an Hsp90-dependent activity of normal or tumor cells.

    摘要翻译： 用于评估分子以鉴定可以作为Hsp90的治疗性抑制剂的分子的方法使用单独或组合的荧光偏振（FP）测定和基于细胞的测定。 FP测定使用荧光标记的Hsp90结合剂，并测量相对于标准品的荧光偏振度。 极化程度的降低表明荧光标记的Hsp90结合剂已经被候选分子完全或部分置换，并且将该分子鉴定为具有作为Hsp90抑制剂的活性。 基于细胞的测定减少的测定是正常或肿瘤细胞的Hsp90依赖性活性。

    HSP90 COMBINATION THERAPY
    19.
    发明申请
    HSP90 COMBINATION THERAPY 审中-公开
    HSP90联合治疗

    公开(公告)号：US20140315929A1

    公开(公告)日：2014-10-23

    申请号：US14113779

    申请日：2012-04-27

    申请人： Gabriela Chiosis

    发明人： Gabriela Chiosis

    IPC分类号： G01N33/50 ,  A61K45/06 ,  G01N33/574 ,  A61K31/52

    CPC分类号： G01N33/5748 ,  A61K31/52 ,  A61K45/06 ,  G01N33/5011 ,  G01N33/5041 ,  A61K2300/00

    摘要： This invention concerns a method for selecting an inhibitor of a cancer-implicated pathway or of a component of a cancer-implicated pathway for coadministration, with an inhibitor of HSP90, to a subject suffering from a cancer which comprises the following steps: (a) contacting a sample containing cancer cells from a subject with an inhibitor of HSP90 or an analog, homolog or derivative of an inhibitor of HSP90 under conditions such that one or more cancer pathway components present in the sample bind to the HSP90 inhibitor or the analog, homolog or derivative of the HSP90 inhibitor; (b) detecting pathway components bound to the HSP90 inhibitor or to the analog, homolog or derivative of the HSP90 inhibitor; (c) analyzing the pathway components detected in step (b) so as to identify a pathway which includes the components detected in step (b) and additional components of such pathway; and (d) selecting an inhibitor of the pathway or of a pathway component identified in step (c). This invention further concerns a method of treating a cancer patient by coadministering an inhibitor of HSP90 and an inhibitor of a cancer-implicated pathway or component thereof.

    摘要翻译： 本发明涉及一种选择癌症相关途径抑制剂或癌症相关途径与抑制剂HSP90共同给药的方法，该方法包括以下步骤：（a） 使来自受试者的含有癌细胞的样品与HSP90的抑制剂或HSP90抑制剂的类似物，同源物或衍生物接触，使得存在于样品中的一种或多种癌症途径成分与HSP90抑制剂或类似物同源物 或HSP90抑制剂的衍生物; （b）检测与HSP90抑制剂或HSP90抑制剂的类似物，同源物或衍生物结合的途径成分; （c）分析在步骤（b）中检测的途径组分，以便鉴定包含步骤（b）中检测到的组分和该途径的其它组分的途径; 和（d）选择步骤（c）中鉴定的途径或途径成分的抑制剂。 本发明还涉及通过共同施用HSP90抑制剂和癌症相关途径或其组分的抑制剂来治疗癌症患者的方法。