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1. 发明申请

US20210379188A1 TARGET VALIDATION AND PROFILING OF THE RNA TARGETS OF SMALL MOLECULES 有权
公开(公告)号：US20210379188A1
公开(公告)日：2021-12-09
申请号：US17284297
申请日：2019-09-26
申请人： The Scripps Research Institute
发明人： Matthew D. Disney
IPC分类号： A61K47/55 , C12N15/11 , A61K31/704
摘要： A method for the precise cellular destruction of an oncogenic non-coding RNA with a RNA-binding small molecule conjugated with bleomycin A5 is described. The method affords reversal of phenotype. Bleomycin A5 was coupled to an RNA-binding molecule that selectively binds the microRNA-96 hairpin precursor (pri-miR-96). By coupling of bleomycin A5's free amine to the RNA-binding molecule, its affinity for binding to pri-miR-96 is >100-fold stronger than to DNA. The conjugate compound selectively cleaves pri-miR-96 in triple negative breast cancer (TNBC) cells. Selective cleavage of pri-miR-96 enhances expression of FOXO1 protein, a pro-apoptotic transcription factor that miR-96 silences, and triggers apoptosis in TNBC cells. No effects were observed in healthy breast epithelial cells. This method provides programmable control for targeting RNA through the selection of an RNA-binding molecule/bleomycin A5 conjugate and provides a facile method of mapping the cellular binding sites of an RNA-binding molecule.

2. 发明授权

US10157261B2 Transcriptome-wide design of selective, bioactive small molecules targeting RNA 有权
公开(公告)号：US10157261B2
公开(公告)日：2018-12-18
申请号：US14911032
申请日：2014-08-08
申请人： The Scripps Research Institute
发明人： Matthew D. Disney , Sai Velagapudi
IPC分类号： G06F19/16 , C07D235/18 , C07D403/14 , C07H15/04 , C07D235/20 , C07H15/234 , G01N33/53 , G06F19/22
摘要： Methods and computer systems are described herein for identifying small molecules that bind to selected RNA structural features (e.g., to RNA secondary structures). Also described are compounds and compositions that modulate RNA function and/or activity.

3. 发明申请

US20180267028A1 Specific Targeting of RNA Expanded Repeat Sequences 审中-公开
公开(公告)号：US20180267028A1
公开(公告)日：2018-09-20
申请号：US15915765
申请日：2018-03-08
申请人： THE SCRIPPS RESEARCH INSTITUTE
发明人： Matthew D. Disney , Lirui Guan , Wang-Yong Yang
IPC分类号： G01N33/53
CPC分类号： G01N33/5308 , A61K48/00 , C07D403/14 , C07D495/04 , C07D519/00 , G01N2500/04 , G01N2500/10
摘要： The present invention provides small molecule compounds that can form covalent adducts with specific sequences of RNA, such as the hairpin loop r(CUG)exp sequence which is a cause of myotonic dystrophy type 1 (DM1), or the r(CGG)exp sequence which is a cause of fragile X-associated tremor/ataxia syndrome (FXTAS); to methods of making the small molecule compounds; and to methods of using the small molecular compounds in the treatment of DM1 or of FXTAS in patients afflicted therewith. The invention further provides a method for identifying an RNA target of a small molecule drug in vivo, using a small molecule drug conjugated to an RNA-reactive crosslinker group and a reporter group, contacting a cell or nucleic acid extract with the small molecule drug conjugate, then separating RNA targets crosslinked to the small molecule drug conjugate by interaction of the affinity group with a complementary affinity group.

4. 发明申请

US20170234859A1 SPECIFIC TARGETING OF RNA EXPANDED REPEAT SEQUENCES 审中-公开
公开(公告)号：US20170234859A1
公开(公告)日：2017-08-17
申请号：US15427288
申请日：2017-02-08
申请人： THE SCRIPPS RESEARCH INSTITUTE
发明人： Matthew D. Disney , Lirui Guan , Wang-Yong Yang
IPC分类号： G01N33/53
CPC分类号： G01N33/5308 , A61K48/00 , C07D403/14 , C07D495/04 , C07D519/00 , G01N2500/04 , G01N2500/10
摘要： The present invention provides small molecule compounds that can form covalent adducts with specific sequences of RNA, such as the hairpin loop r(CUG)exp sequence which is a cause of myotonic dystrophy type 1 (DM1), or the r(CGG)exp sequence which is a cause of fragile X-associated tremor/ataxia syndrome (FXTAS); to methods of making the small molecule compounds; and to methods of using the small molecular compounds in the treatment of DM1 or of FXTAS in patients afflicted therewith. The invention further provides a method for identifying an RNA target of a small molecule drug in vivo, using a small molecule drug conjugated to an RNA-reactive crosslinker group and a reporter group, contacting a cell or nucleic acid extract with the small molecule drug conjugate, then separating RNA targets crosslinked to the small molecule drug conjugate by interaction of the affinity group with a complementary affinity group.

5. 发明授权

US09586944B2 Specific targeting of RNA expanded repeat sequences 有权
标题翻译： RNA扩增重复序列的特异性靶向
公开(公告)号：US09586944B2
公开(公告)日：2017-03-07
申请号：US14904999
申请日：2014-07-15
申请人： THE SCRIPPS RESEARCH INSTITUTE
发明人： Matthew D. Disney , Lirui Guan , Wang-Yong Yang
IPC分类号： A61K48/00 , C07D403/14 , C07D495/04 , C07D519/00
CPC分类号： G01N33/5308 , A61K48/00 , C07D403/14 , C07D495/04 , C07D519/00 , G01N2500/04 , G01N2500/10
摘要： The present invention provides small molecule compounds that can form covalent adducts with specific sequences of RNA, such as the hairpin loop r(CUG)exp sequence which is a cause of myotonic dystrophy type 1 (DM1), or the r(CGG)exp sequence which is a cause of fragile X-associated tremor/ataxia syndrome (FXTAS); to methods of making the small molecule compounds; and to methods of using the small molecular compounds in the treatment of DM1 or of FXTAS in patients afflicted therewith. The invention further provides a method for identifying an RNA target of a small molecule drug in vivo, using a small molecule drug conjugated to an RNA-reactive crosslinker group and a reporter group, contacting a cell or nucleic acid extract with the small molecule drug conjugate, then separating RNA targets crosslinked to the small molecule drug conjugate by interaction of the affinity group with a complementary affinity group.
摘要翻译：本发明提供可以形成具有特定RNA序列的共价加合物的小分子化合物，例如作为强直性营养不良型1（DM1）或r（CGG）exp序列的发夹环r（CUG）exp序列这是造成X型相关震颤/共济失调综合征（FXTAS）的易感因素。制备小分子化合物的方法; 以及使用小分子化合物治疗患有DM1或FXTAS的患者的方法。本发明还提供了使用与RNA反应性交联剂基团和报道基团缀合的小分子药物，使细胞或核酸提取物与小分子药物缀合物接触的方法来鉴定体内小分子药物的RNA靶标，然后通过亲和基团与互补亲和基团的相互作用分离与小分子药物偶联物交联的RNA靶标。

6. 发明申请

US20150307487A1 SMALL MOLECULES TARGETING REPEAT r(CGG) SEQUENCES 有权
标题翻译：小分子靶向重复序列（CGG）序列
公开(公告)号：US20150307487A1
公开(公告)日：2015-10-29
申请号：US14424761
申请日：2013-08-30
申请人： THE SCRIPPS RESEARCH INSTITUTE
发明人： Matthew D. Disney , Biao Liu , Jessica L. Childs-Disney , Wang-Yong Yang
IPC分类号： C07D471/04 , A61K47/48 , C07D519/00
CPC分类号： C07D471/04 , A61K31/475 , A61K47/65 , C07D519/00
摘要： The invention provides a series of bioactive small molecules that target expanded r(CGG) repeats, termed r(CGG)exp, that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium, binds the 5′CG/3′GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Specifically, dimeric compounds incorporating two 9-hydroxyellipticine analog structures can even more potently bind the 5′CGG/3′GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Structure-activity relationships (SAR) studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG) repeats, such as r(CGG)exp. Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)exp-protein aggregates.
摘要翻译：本发明提供一系列生物活性小分子，其靶向引起脆性X相关性震颤共济失调综合征（FXTAS）的扩增的r（CGG）重复，称为r（CGG）exp。通过使用与相互作用的化学型和RNA基序的信息来鉴定该化合物。具体地，9-羟基-5,11-二甲基-2-（2-（哌啶-1-基）乙基）-6H-吡啶并[4,3-b]咔唑-2-氧化物结合5'CG / 3 r（CGG）中的GGC基序表达并破坏毒性r（CGG）exp蛋白复合物。具体来说，结合两个9-羟基椭圆星类似物结构的二聚化合物甚至可以更有效地结合r（CGG）exp中的5'CGG / 3'GGC基序并破坏毒性r（CGG）exp蛋白复合物。结构 - 活性关系（SAR）研究确定烷基化的吡啶基和酚侧链是驱动r（CGG）重复的分子识别的重要的化学型，例如r（CGG）exp。重要的是，该化合物在FXTAS模型细胞系统中是有效的，如通过其改善FXTAS相关的前mRNA剪接缺陷并减少r（CGG）exp蛋白聚集体的大小和数量的能力所证明的。

7. 发明申请

US20210102200A1 SMALL MOLECULE TARGETED RECRUITMENT OF A NUCLEASE TO RNA 有权
公开(公告)号：US20210102200A1
公开(公告)日：2021-04-08
申请号：US17050219
申请日：2019-04-24
申请人： The Scripps Research Institute
发明人： Matthew D. Disney
IPC分类号： C12N15/11
摘要： Provided herein are compounds that selectively bind and cleave RNA. In various embodiments, the disclosure provides chemical compounds effective as ribonuclease targeting chimeras (RIBOTACs), that target the endogenous enzyme RNase L to selectively cleave the RNA in a living cell. These compounds are useful in the treatment of diseases, e.g., the treatment of breast cancer.

8. 发明授权

US10471057B2 Toxic RNA inhibitors self-assembled in situ 有权
公开(公告)号：US10471057B2
公开(公告)日：2019-11-12
申请号：US16266832
申请日：2019-02-04
申请人： THE SCRIPPS RESEARCH INSTITUTE
发明人： Matthew D. Disney , Suzanne G. Rzuczek
IPC分类号： C12N15/10 , A61K31/496 , A61K31/702 , A61K38/07 , A61K38/08 , A61K47/54 , A61K47/55
摘要： Potent modulators of RNA function can be assembled in cellulo by using the cell as a reaction vessel and a disease-causing RNA as a catalyst. When designing small molecule effectors of function, a balance between permeability and potency must be struck. Low molecular weight compounds are more permeable while higher molecular weight compounds are more potent. The advantages of both types of compounds could be synergized if low molecular weight molecules could be transformed into potent, multivalent ligands via a reaction catalyzed by binding to a target in cells expressing a genetic defect. We demonstrate that this approach is indeed viable in cellulo. Small molecule modules with precisely positioned alkyne and azide moieties bind adjacent internal loops in r(CCUG)exp, the causative agent of myotonic dystrophy type 2 (DM2), and are transformed into oligomeric, potent inhibitors of DM2 RNA dysfunction via a 1,3 Huisgen dipolar cycloaddition reaction, a variant of click chemistry. Additionally, we show that this approach is applicable to the r(CUG) repeating RNA that causes myotonic dystrophy type 1 (DM1). The click chemistry approach also allows for FRET sensors to be synthesized on-site by using r(CUG) repeats as a catalyst. Furthermore it is shown that small molecule binding sites in patient-derived cells can be identified by using reactive approaches termed Chem-CLIP and Chem-CLIP-Map. Lastly, it is shown that small molecules that target r(CUG) expansions can be designed to cleave this RNA by appending a small molecule with a nucleic acid cleaving module.

9. 发明申请

US20160188791A1 TRANSCRIPTOME-WIDE DESIGN OF SELECTIVE, BIOACTIVE SMALL MOLECULES TARGETING RNA 审中-公开
标题翻译：选择性，生物活性小分子靶向RNA的转录式设计
公开(公告)号：US20160188791A1
公开(公告)日：2016-06-30
申请号：US14911032
申请日：2014-08-08
申请人： The Scripps Research Institute
发明人： Matthew D. Disney , Sai Velagapudi
IPC分类号： G06F19/16 , C07D235/20 , G01N33/53 , C07D403/14 , G06F19/22 , C07D235/18 , C07H15/234
CPC分类号： G06F19/16 , C07D235/18 , C07D235/20 , C07D403/14 , C07H15/04 , C07H15/234 , G01N33/5308 , G01N2500/04 , G06F19/22
摘要： Methods and computer systems are described herein for identifying small molecules that bind to selected RNA structural features (e.g., to RNA secondary structures). Also described are compounds and compositions that modulate RNA function and/or activity.
摘要翻译：本文描述了用于鉴定结合所选RNA结构特征（例如，到RNA二级结构）的小分子的方法和计算机系统。还描述了调节RNA功能和/或活性的化合物和组合物。

10. 发明申请

US20190151310A1 TOXIC RNA INHIBITORS SELF-ASSEMBLED IN SITU 审中-公开
公开(公告)号：US20190151310A1
公开(公告)日：2019-05-23
申请号：US16266832
申请日：2019-02-04
申请人： THE SCRIPPS RESEARCH INSTITUTE
发明人： Matthew D. Disney , Suzanne G. Rzuczek
IPC分类号： A61K31/496 , A61K47/54 , A61K38/08 , A61K31/702 , A61K47/55 , A61K38/07
CPC分类号： A61K31/496 , A61K31/702 , A61K38/07 , A61K38/08 , A61K47/549 , A61K47/55 , A61K47/557
摘要： Potent modulators of RNA function can be assembled in cellulo by using the cell as a reaction vessel and a disease-causing RNA as a catalyst. When designing small molecule effectors of function, a balance between permeability and potency must be struck. Low molecular weight compounds are more permeable while higher molecular weight compounds are more potent. The advantages of both types of compounds could be synergized if low molecular weight molecules could be transformed into potent, multivalent ligands via a reaction catalyzed by binding to a target in cells expressing a genetic defect. We demonstrate that this approach is indeed viable in cellulo. Small molecule modules with precisely positioned alkyne and azide moieties bind adjacent internal loops in r(CCUG)exp, the causative agent of myotonic dystrophy type 2 (DM2), and are transformed into oligomeric, potent inhibitors of DM2 RNA dysfunction via a 1,3 Huisgen dipolar cycloaddition reaction, a variant of click chemistry. Additionally, we show that this approach is applicable to the r(CUG) repeating RNA that causes myotonic dystrophy type 1 (DM1). The click chemistry approach also allows for FRET sensors to be synthesized on-site by using r(CUG) repeats as a catalyst. Furthermore it is shown that small molecule binding sites in patient-derived cells can be identified by using reactive approaches termed Chem-CLIP and Chem-CLIP-Map. Lastly, it is shown that small molecules that target r(CUG) expansions can be designed to cleave this RNA by appending a small molecule with a nucleic acid cleaving module.

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