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1. 发明申请

WO2005115354A3 COMPOSITIONS AND METHODS FOR BONE FORMATION AND REMODELING 审中-公开
标题翻译：用于骨形成和重建的组合物和方法
公开(公告)号：WO2005115354A3
公开(公告)日：2007-09-13
申请号：PCT/US2005017199
申请日：2005-05-18
申请人： ENZO THERAPEUTICS INC , ZHANG YAZHOU , LIU PENG , LI XIAOFENG , ZHANG JIE , SHAN JUFANG , ENGELHARDT DEAN , WU DIANQING
发明人： ZHANG YAZHOU , LIU PENG , LI XIAOFENG , ZHANG JIE , SHAN JUFANG , ENGELHARDT DEAN , WU DIANQING
IPC分类号： A61P19/00 , A61K9/68 , A61P19/08 , A61P19/10 , G01N33/48 , G01N33/50 , G01N33/53 , G01N33/68 , G06F19/00
CPC分类号： G01N33/6893 , A61K38/00 , G01N33/6887 , G01N2500/00 , G01N2800/10 , G01N2800/108
摘要： The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an increase in Wnt activity in osteoblastls by reducing the numnber of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.
摘要翻译：研究了Wnt共同受体LRP5的高骨量（HBM）突变（G171V）调节规范Wnt信号传导的机制。以前显示突变可以降低Dkk蛋白-1介导的拮抗作用，这表明G171位于第一个YWTD重复结构域可能是Dkk蛋白介导的拮抗作用的原因。然而，我们发现第三个YWTD重复，但不是第一个重复结构域，是DKK1介导的拮抗作用所必需的。相反，我们发现G171V突变破坏了LRP5与Mesd的相互作用，Mesd是细胞表面上LRP5 / 6分子的伴侣蛋白。尽管细胞表面LRP5分子水平的降低导致旁分泌范例中Wnt信号传导的降低，但突变似乎不影响共表达Wnt在自分泌范式中的活性。连同观察到，成骨细胞产生自分泌标准Wnt，Wnt7b，并且该骨细胞产生旁分泌Dkk1，我们认为G171V突变可能通过减少旁分泌Dkk1的靶标的数目来拮抗而引起成骨细胞中Wnt活性的增加而不影响成骨细胞自分泌Wnt的活性。

2. 发明公开

EP1758562A4 COMPOSITIONS AND METHODS FOR BONE FORMATION AND REMODELING 有权
标题翻译：骨打破和重塑的组合物和方法
公开(公告)号：EP1758562A4
公开(公告)日：2009-07-22
申请号：EP05751764
申请日：2005-05-18
申请人： ENZO THERAPEUTICS INC , ZHANG YAZHOU , LIU PENG , LI XIAOFENG , ZHANG JIE , SHAN JUFANG , ENGELHARDT DEAN
发明人： WU DIANQING , ZHANG YAZHOU , LIU PENG , LI XIAOFENG , ZHANG JIE , SHAN JUFANG , ENGELHARDT DEAN
IPC分类号： A61P19/00 , A61K9/68 , A61K31/00 , A61P19/08 , A61P19/10 , G01N33/48 , G01N33/50 , G01N33/53 , G01N33/68 , G06F19/00
CPC分类号： G01N33/6893 , A61K38/00 , G01N33/6887 , G01N2500/00 , G01N2800/10 , G01N2800/108

3. 发明公开

EP1755643A4 COMPOSITIONS AND METHODS FOR THE STIMULATION OR ENHANCEMENT OF BONE FORMATION AND THE SELF-RENEWAL OF CELLS 审中-公开
标题翻译：组合物和方法刺激或增加骨形成和细胞的自我更新
公开(公告)号：EP1755643A4
公开(公告)日：2009-08-19
申请号：EP05758035
申请日：2005-05-18
申请人： ENZO THERAPEUTICS INC , LI XIAOFENG , LIU PENG , LIU WENZHONG , ENGELHARDT DEAN
发明人： WU DIANQING , LI XIAOFENG , LIU PENG , LIU WENZHONG , ENGELHARDT DEAN
IPC分类号： A61K38/00 , A61K38/17 , A61P19/00 , A61P19/08 , A61P19/10
CPC分类号： A61K38/1709

4. 发明申请

WO2005112981A2 COMPOSITIONS AND METHODS FOR THE STIMULATION OR ENHANCEMENT OF BONE FORMATION AND THE SELF-RENEWAL OF CELLS 审中-公开
标题翻译：刺激或增强骨形成和细胞自我更新的组合物和方法
公开(公告)号：WO2005112981A2
公开(公告)日：2005-12-01
申请号：PCT/US2005017420
申请日：2005-05-18
申请人： ENZO THERAPEUTICS INC , LI XIAOFENG , LIU PENG , LIU WENZHONG , ENGELHARDT DEAN
发明人： WU DIANQING , LI XIAOFENG , LIU PENG , LIU WENZHONG , ENGELHARDT DEAN
IPC分类号： A61K38/17
CPC分类号： A61K38/1709
摘要： Compositions and methods for the treatment of bon diseases, bone fractures, bone injuries and other bone abnormalities involving the use of Dkk protein, a Wnt antagonist, a Wnt inhibitor, or any other related protein for the stimulation or enhancement of mineralization and for stimulating the renewal of cells. One Dkk protein, Dickkopf-2 (Dkk-2) acts to stimulate bone formation independently of Wnt proteins which may be inhibited and/or antagonized by Dkk-2. Dkk-2 displayed enhanced specific targeting ability and enhanced biological activity in stimulating or enhancing mineralization. Dkk-2 also played a role in the differentiation and self-renewal of hematopoietic stem cells and mesenchymal stem cells, particularly in osteoblastogenesis and osteoclastogenesis.
摘要翻译：用于治疗Bon疾病，骨折，骨损伤和涉及使用Dkk蛋白，Wnt拮抗剂，Wnt抑制剂或任何其他相关蛋白质的骨骼异常的组合物和方法，用于刺激或增强矿化和刺激细胞更新一种Dkk蛋白Dickkopf-2（Dkk-2）可以独立于可被Dkk-2抑制和/或拮抗的Wnt蛋白质刺激骨形成。 Dkk-2显示出增强的特异性靶向能力和增强的刺激或增强矿化的生物活性。 Dkk-2也在造血干细胞和间充质干细胞的分化和自我更新中发挥作用，特别是在成骨细胞形成和破骨细胞发生过程中。

5. 发明申请

WO2006107719A2 COMPOSITIONS AND METHODS FOR THE INHIBITION OF DISHEVELLED PROTEINS 审中-公开
标题翻译：抑制蛋白质的组合物和方法
公开(公告)号：WO2006107719A2
公开(公告)日：2006-10-12
申请号：PCT/US2006011754
申请日：2006-03-31
申请人： ENZO BIOCHEM INC , ZHENG JIE , SHAN JUFANG , WU DIANQING
发明人： ZHENG JIE , SHAN JUFANG , WU DIANQING
IPC分类号： A61K38/17
CPC分类号： A61K31/00 , A61K31/164 , C07K1/00 , C40B30/02
摘要： The Wnt signaling pathways are involved in embryo development as well as in M tumorigenesis. Dishevelled (DvI) tra®'duces Wnt signals from the receptor Frizzled (Fz) to downstream components in canonical and non-canonical Wnt signaling pathways, and the DvI , PDZ domain plays an essential role in both pathways, and the DvI PDZ .domain binds directly to Fz receptors. In the present invention using NMR-assisted virtual ligand screening, several compounds were identified and were found to bind to the DvI PDZ domain. Molecular dynamics simulation was used to analyze the binding between the PDZ domain and these compounds in detail. These compounds provide a basis for rational design of high-affinity inhibitors of the PDZ domain, which can block Wnt signaling by interrupting the Fz-DvI interaction.
摘要翻译： Wnt信号通路参与胚胎发育以及M肿瘤发生。不规则（DvI）tra®将Wnt信号从受体卷曲（Fz）引发到规范和非规范Wnt信号通路中的下游组分，DvI，PDZ结构域在两个途径中起重要作用，DvI PDZ。直接与Fz受体结合。在使用NMR辅助的虚拟配体筛选的本发明中，鉴定出几种化合物，并且发现其与DvI PDZ结构域结合。分子动力学模拟用于详细分析PDZ结构域与这些化合物的结合。这些化合物为PDZ结构域的高亲和力抑制剂的合理设计提供了依据，可以通过中断Fz-DvI相互作用来阻断Wnt信号。

6. 发明专利

CA2567023C COMPOSITIONS AND METHODS FOR BONE FORMATION AND REMODELING 未知
公开(公告)号：CA2567023C
公开(公告)日：2012-07-03
申请号：CA2567023
申请日：2005-05-18
申请人： ENZO THERAPEUTICS INC
发明人： ZHANG YAZHOU , LIU PENG , LI XIAOFENG , ZHANG JIE , SHAN JUFANG , ENGELHARDT DEAN , WU DIANQING
IPC分类号： A61K31/538 , A61K9/68 , A61K31/185 , A61K31/4709 , A61K45/00 , A61P19/08 , A61P31/12 , C40B30/02 , G01N33/48 , G01N33/50 , G01N33/53 , G01N33/68 , G06F19/00
摘要： The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an increase in Wnt activity in osteoblastls by reducing the numnber of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.

7. 发明专利

CA2566848C COMPOSITIONS COMPRISING DKK2 AND METHODS FOR USE THEREOF FOR THE STIMULATION OR ENHANCEMENT OF BONE FORMATION AND THE SELF-RENEWAL OF CELLS 未知
公开(公告)号：CA2566848C
公开(公告)日：2016-07-12
申请号：CA2566848
申请日：2005-05-18
申请人： ENZO THERAPEUTICS INC
发明人： LI XIAOFENG , LIU PENG , LIU WENZHONG , ENGELHARDT DEAN , WU DIANQING
IPC分类号： A61K38/17
摘要： Compositions and methods for the treatment of bon diseases, bone fractures, bone injuries and other bone abnormalities involving the use of Dkk protein, a Wnt antagonist, a Wnt inhibitor, or any other related protein for the stimulation or enhancement of mineralization and for stimulating the renewal of cells. One Dkk protein, Dickkopf-2 (Dkk-2) acts to stimulate bone formation independently of Wnt proteins which may be inhibited and/or antagonized by Dkk-2. Dkk-2 displayed enhanced specific targeting ability and enhanced biological activity in stimulating or enhancing mineralization. Dkk-2 also played a role in the differentiation and self-renewal of hematopoietic stem cells and mesenchymal stem cells, particularly in osteoblastogenesis and osteoclastogenesis.

8. 发明专利

CA2772033C COMPOSITIONS AND METHODS FOR BONE FORMATION AND REMODELING 未知
公开(公告)号：CA2772033C
公开(公告)日：2016-05-17
申请号：CA2772033
申请日：2005-05-18
申请人： ENZO THERAPEUTICS INC
发明人： ZHANG YAZHOU , LIU PENG , LI XIAOFENG , ZHANG JIE , SHAN JUFANG , ENGELHARDT DEAN , WU DIANQING
IPC分类号： A61K35/28 , A61K9/68 , A61K31/185 , A61K31/4709 , A61K31/538 , A61P31/12 , C12N5/071 , C12N5/077 , C12N5/078 , C40B30/02 , G01N33/48 , G01N33/50 , G01N33/53 , G01N33/68 , G06F19/00
摘要： The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein- mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a praracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autorcine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an incrase in Wnt activity in osteoblasts by reducing the number of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.

9. 发明专利

CA2772029C COMPOSITIONS AND METHODS FOR BONE FORMATION AND REMODELING 未知
公开(公告)号：CA2772029C
公开(公告)日：2016-05-17
申请号：CA2772029
申请日：2005-05-18
申请人： ENZO THERAPEUTICS INC
发明人： ZHANG YAZHOU , LIU PENG , LI XIAOFENG , ZHANG JIE , SHAN JUFANG , ENGELHARDT DEAN , WU DIANQING
IPC分类号： A61K35/12 , A61K9/68 , A61K31/185 , A61K31/4709 , A61K31/538 , A61K35/28 , A61P19/08 , A61P31/12 , C12N5/071 , C12N5/077 , C12N5/0783 , C40B30/02 , G01N33/48 , G01N33/50 , G01N33/53 , G01N33/68 , G06F19/00
摘要： The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein- mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a praracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autorcine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an incrase in Wnt activity in osteoblasts by reducing the number of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.

10. 发明专利

CA2771941C COMPOSITIONS AND METHODS FOR BONE FORMATION AND REMODELING 未知
公开(公告)号：CA2771941C
公开(公告)日：2015-03-31
申请号：CA2771941
申请日：2005-05-18
申请人： ENZO THERAPEUTICS INC
发明人： ZHANG YAZHOU , LIU PENG , LI XIAOFENG , ZHANG JIE , ENGELHARDT DEAN , SHAN JUFANG , WU DIANQING
IPC分类号： A61K31/538 , A61K9/68 , A61K31/185 , A61K31/4709 , A61P35/00 , C40B30/02 , G01N33/48 , G01N33/50 , G01N33/53 , G01N33/68 , G06F19/00
摘要： The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein- 1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein- mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a praracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autorcine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an incrase in Wnt activity in osteoblasts by reducing the number of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.

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