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1.发明申请STRUCTURE OF THE FARNESOID X RECEPTOR LIGAND BINDING DOMAIN AND METHODS OF USE THEREFOR 失效FARNESOID X受体配体结合域的结构及其使用方法公开(公告)号：US20110018866A1
公开(公告)日：2011-01-27
申请号：US12686347
申请日：2010-01-12
申请人： Michael R. Downes , Mark A. Verdicia , Joseph P. Noel , Ronald M. Evans , Lindsey J. Bowman , Marianne Bowman
发明人： Michael R. Downes , Mark A. Verdicia , Joseph P. Noel , Ronald M. Evans , Lindsey J. Bowman , Marianne Bowman
IPC分类号： C07C229/44 , C07K14/72 , A61K38/16 , A61K31/216 , C07D317/58 , A61K31/36 , C07J9/00 , A61K31/575 , C07D261/08 , A61K31/42 , G06G7/58 , G06T15/00
CPC分类号： C07K14/70567 , C07K2299/00 , G01N33/743 , G01N2500/00 , G06F19/16 , G06F19/706
摘要： The present invention provides compositions comprising the ligand binding domain (LBD) of a farnesoid X receptor (FXR) in crystalline form. In alternative embodiments, the LBD of FXR is complexed with a ligand therefor. There are provided high resolution structures of FXR complexed with a novel high affinity agonist fexaramine. The discovered structure of a FXR LBD provides the first three-dimensional view of the structural basis for FXR ligand binding. The present invention further provides a computer for producing a time-dimensional representation of FXR or a complex thereof, and a computer for determining at least a portion of the structure coordinates of FXR or a complex thereof. The present invention further provides methods of using this structural information to predict molecules capable of binding to FXR; to identify compounds with agonist, antagonist or partial agonist activity for FXR; and to determine whether a test compound is capable of binding to the LBD of FXR. The present invention further provides compositions comprising compounds identified by such invention methods.
摘要翻译： 本发明提供了包含结晶形式的法呢甾X受体（FXR）的配体结合结构域（LBD）的组合物。 在替代实施方案中，FXR的LBD与其配体复合。 提供了与新型高亲和力激动剂福沙康胺复合的FXR的高分辨率结构。 所发现的FXR LBD的结构提供了FXR配体结合的结构基础的第一个三维视图。 本发明还提供一种用于产生FXR或其复数的时间维度表示的计算机，以及用于确定FXR或其复数的结构坐标的至少一部分的计算机。 本发明还提供使用该结构信息来预测能够结合FXR的分子的方法; 识别FXR激动剂，拮抗剂或部分激动剂活性的化合物; 并确定测试化合物是否能够结合FXR的LBD。 本发明还提供包含通过本发明方法鉴定的化合物的组合物。
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2.发明授权SMRT co-repressors, transcriptional co-repressors that interact with nuclear hormone receptors 失效SMRT共同抑制因子，与核激素受体相互作用的转录共抑制因子公开(公告)号：US07314747B1
公开(公告)日：2008-01-01
申请号：US09522753
申请日：2000-03-10
CPC分类号： C07K14/4703 , G01N33/74 , G01N2500/00
摘要： The present invention relates to isolated polynucleotides encoding a family of silencing mediators of retinoic acid and thyroid hormone receptor (SMRT) isoforms, including vertebrate and invertebrate isoforms thereof. The invention also relates to polypeptide SMRT co-repressors encoded by invention SMRT polynucleotides, and to peptide portions thereof that can modulate transcriptional potential of a nuclear receptor. In addition, the invention relates to chimeric molecules and to complexes containing a SMRT co-repressor or peptide portion thereof, to antibodies that specifically bind such compositions, and to methods for identifying an agent that modulates the repressor potential of a SMRT co-repressor. The invention also provides methods for identifying an agent that modulates a function of a SMRT co-repressor; for modulating the transcriptional potential of a nuclear receptor in a cell using the compositions of the invention; and for identifying a molecule that interacts specifically with a SMRT co-repressor.
摘要翻译： 本发明涉及编码维甲酸和甲状腺激素受体（SMRT）同种型的沉默介导家族的分离多核苷酸，包括脊椎动物和无脊椎动物同种型。 本发明还涉及由本发明的SMRT多核苷酸编码的多肽SMRT共抑制子及其可调节核受体的转录潜力的肽部分。 此外，本发明涉及嵌合分子和含有SMRT共抑制子或其肽部分的复合物与特异性结合该组合物的抗体以及用于鉴定调节SMRT共抑制因子的阻遏物潜力的试剂的方法。 本发明还提供了用于鉴定调节SMRT共抑制子功能的试剂的方法; 用于使用本发明的组合物调节细胞中核受体的转录电位; 并用于鉴定与SMRT共抑制子特异性相互作用的分子。
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3.发明授权Structure of the farnesoid X receptor ligand binding domain and methods of use therefor 失效法呢酯X受体配体结合域的结构及其用途公开(公告)号：US08212006B2
公开(公告)日：2012-07-03
申请号：US12686347
申请日：2010-01-12
申请人： Michael R. Downes , Mark A. Verdicia , Joseph P. Noel , Ronald M. Evans , Lindsey J. Bowman , Marianne Bowman
发明人： Michael R. Downes , Mark A. Verdicia , Joseph P. Noel , Ronald M. Evans , Lindsey J. Bowman , Marianne Bowman
CPC分类号： C07K14/70567 , C07K2299/00 , G01N33/743 , G01N2500/00 , G06F19/16 , G06F19/706
摘要： The present invention provides compositions comprising the ligand binding domain (LBD) of a farnesoid X receptor (FXR) in crystalline form. In alternative embodiments, the LBD of FXR is complexed with a ligand therefor. There are provided high resolution structures of FXR complexed with a novel high affinity agonist fexaramine. The discovered structure of a FXR LBD provides the first three-dimensional view of the structural basis for FXR ligand binding. The present invention further provides a computer for producing a time-dimensional representation of FXR or a complex thereof, and a computer for determining at least a portion of the structure coordinates of FXR or a complex thereof. The present invention further provides methods of using this structural information to predict molecules capable of binding to FXR; to identify compounds with agonist, antagonist or partial agonist activity for FXR; and to determine whether a test compound is capable of binding to the LBD of FXR. The present invention further provides compositions comprising compounds identified by such invention methods.
摘要翻译： 本发明提供了包含结晶形式的法呢甾X受体（FXR）的配体结合结构域（LBD）的组合物。 在替代实施方案中，FXR的LBD与其配体复合。 提供了与新型高亲和力激动剂福沙康胺复合的FXR的高分辨率结构。 所发现的FXR LBD的结构提供了FXR配体结合的结构基础的第一个三维视图。 本发明还提供一种用于产生FXR或其复数的时间维度表示的计算机，以及用于确定FXR或其复数的结构坐标的至少一部分的计算机。 本发明还提供使用该结构信息来预测能够结合FXR的分子的方法; 识别FXR激动剂，拮抗剂或部分激动剂活性的化合物; 并确定测试化合物是否能够结合FXR的LBD。 本发明还提供包含通过本发明方法鉴定的化合物的组合物。
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4.发明授权公开(公告)号：US07671085B2
公开(公告)日：2010-03-02
申请号：US10535043
申请日：2003-11-14
申请人： Michael R. Downes , Ronald M. Evans
发明人： Michael R. Downes , Ronald M. Evans
CPC分类号： C07D311/94 , A61K31/16 , A61K31/353 , A61K31/44 , A61K31/4433 , C07C233/54 , C07C233/63 , C07C233/81 , C07C237/22 , C07C275/42 , C07C309/66 , C07C323/40 , C07C2601/02 , C07C2601/04 , C07C2601/08 , C07C2601/14 , C07D213/40 , C07D277/28 , C07D307/46 , C07D311/04 , C07D311/22 , C07D311/64 , C07D311/68 , C07D317/58 , C07D333/20 , C07D333/22 , C07D407/12 , C07D409/12
摘要： The efficient regulation of cholesterol synthesis, metabolism, acquisition, and transport is an essential component of lipid homeostasis. The farnesoid X receptor (FXR) is a transcriptional sensor for bile acids, the primary product of cholesterol metabolism. Accordingly, the development of potent, selective, small molecule agonists, partial agonists, and antagonists of FXR would be an important step in further deconvoluting FXR physiology. In accordance with the present invention, the identification of novel potent FXR activators is described. Two derivatives of invention compounds, bearing stilbene or biaryl moieties, contain members that are the most potent FXR agonists reported to date in cell-based assays. These compounds are useful as chemical tools to further define the physiological role of FXR as well as therapeutic leads for the treatment of diseases linked to cholesterol, bile acids and their metabolism and homeostasis.
摘要翻译： 胆固醇合成，代谢，获取和运输的有效调节是脂质体内平衡的重要组成部分。 法呢蛋白X受体（FXR）是胆汁酸的转录传感器，胆汁酸是胆固醇代谢的主要产物。 因此，FXR的有效的，选择性的，小分子激动剂，部分激动剂和拮抗剂的开发将是进一步去卷积FXR生理学中的重要步骤。 根据本发明，描述了新型有效的FXR活化剂的鉴定。 携带二苯乙烯或联芳基部分的本发明化合物的两种衍生物含有迄今为止基于细胞的测定中报道的最有效的FXR激动剂的成员。 这些化合物可用作进一步定义FXR的生理作用以及用于治疗与胆固醇，胆汁酸及其代谢和体内平衡相关的疾病的治疗用途的化学工具。
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5.发明授权Structure of the farnesoid X receptor ligand binding domain and methods of use therefor 失效法呢酯X受体配体结合域的结构及其用途公开(公告)号：US07647217B2
公开(公告)日：2010-01-12
申请号：US10535042
申请日：2003-11-14
申请人： Michael R Downes , Mark A. Verdicia , Joseph P. Noel , Ronald M. Evans , Lindsey J. Bowman , Marianne Bowman
发明人： Michael R Downes , Mark A. Verdicia , Joseph P. Noel , Ronald M. Evans , Lindsey J. Bowman , Marianne Bowman
CPC分类号： C07K14/70567 , C07K2299/00 , G01N33/743 , G01N2500/00 , G06F19/16 , G06F19/706
摘要： The present invention provides compositions comprising the ligand binding domain (LBD) of a farnesoid X receptor (FXR) in crystalline form. In alternative embodiments, the LBD of FXR is complexed with a ligand therefor. There are provided high resolution structures of FXR complexed with a novel high affinity agonist, fexaramine. The discovered structure of a FXR LBD provides the first three-dimensional view of the structural basis for FXR ligand binding. The present invention further provides a computer for producing a three-dimensional representation of FXR or a complex thereof, and a computer for determining at least a portion of the structure coordinates of FXR or a complex thereof. The present invention further provides methods of using this structural information to predict molecules capable of binding to FXR; to identify compounds with agonist, antagonist or partial agonist activity for FXR; and to determine whether a test compound is capable of binding to the LBD of FXR. The present invention further provides compositions comprising compounds identified by such invention methods.
摘要翻译： 本发明提供了包含结晶形式的法呢甾X受体（FXR）的配体结合结构域（LBD）的组合物。 在替代实施方案中，FXR的LBD与其配体复合。 提供了与新型高亲和力激动剂fexaramine复合的FXR的高分辨率结构。 所发现的FXR LBD的结构提供了FXR配体结合的结构基础的第一个三维视图。 本发明还提供一种用于产生FXR或其复数的三维表示的计算机，以及用于确定FXR的结构坐标的至少一部分或其复合体的计算机。 本发明还提供使用该结构信息来预测能够结合FXR的分子的方法; 识别FXR激动剂，拮抗剂或部分激动剂活性的化合物; 并确定测试化合物是否能够结合FXR的LBD。 本发明还提供包含通过本发明方法鉴定的化合物的组合物。
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