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    SMALL MOLECULES TARGETING REPEAT r(CGG) SEQUENCES
    1.
    发明申请
    SMALL MOLECULES TARGETING REPEAT r(CGG) SEQUENCES 审中-公开

    公开(公告)号：US20170152261A1

    公开(公告)日：2017-06-01

    申请号：US15412231

    申请日：2017-01-23

    申请人： Matthew D. Disney ,  Biao Liu ,  Jessica L. Childs-Disney ,  Wang-Yong Yang

    发明人： Matthew D. Disney ,  Biao Liu ,  Jessica L. Childs-Disney ,  Wang-Yong Yang

    IPC分类号： C07D471/04 ,  A61K31/475

    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′CGG/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.

    SPECIFIC TARGETING OF RNA EXPANDED REPEAT SEQUENCES
    5.
    发明申请
    SPECIFIC TARGETING OF RNA EXPANDED REPEAT SEQUENCES 有权
    RNA扩增重复序列的特异性靶向

    公开(公告)号：US20160257669A1

    公开(公告)日：2016-09-08

    申请号：US14904999

    申请日：2014-07-15

    申请人： Matthew D. DISNEY ,  Lirui GUAN ,  Wang-Yong YANG ,  THE SCRIPPS RESEARCH INSTITUTE

    发明人： Matthew D. Disney ,  Lirui Guan ,  Wang-Yong Yang

    IPC分类号： C07D403/14 ,  C07D495/04

    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。

    C-lysine conjugates as pH-controlled, light-activated reagents for double stranded DNA cleavage and associated methods
    6.
    发明授权
    C-lysine conjugates as pH-controlled, light-activated reagents for double stranded DNA cleavage and associated methods 有权
    作为用于双链DNA切割的pH控制的光活化试剂和相关方法的C-赖氨酸缀合物

    公开(公告)号：US08334403B1

    公开(公告)日：2012-12-18

    申请号：US12640877

    申请日：2009-12-17

    申请人： Igor Alabugin ,  Serguei Kovalenko ,  Wang Yong Yang ,  Kerry Gilmore ,  Boris Breiner

    发明人： Igor Alabugin ,  Serguei Kovalenko ,  Wang Yong Yang ,  Kerry Gilmore ,  Boris Breiner

    IPC分类号： C07C229/00 ,  C12Q1/68

    CPC分类号： C12N15/10 ,  A61K41/0042 ,  C12Q1/68 ,  C12Q2523/107 ,  C12Q2523/319 ,  C12Q2527/119

    摘要： Compounds and methods for double-stranded DNA cleavage of light-activated lysine conjugates are enhanced at the slightly acidic pH suitable for selective targeting of cancer cells by the presence of two amino groups of different basicities. The first amino group plays an auxiliary role enhancing solubility and affinity to DNA whereas the second amino group which is positioned next to the light-activated DNA-cleaver undergoes protonation at the desired pH threshold. Protonation results in two synergetic effects which account for the increased DNA-cleaving ability at the lower pH: tighter binding to DNA at the lower pH; and the unproductive pathway which quenches the excited state of the photocleaver through intramolecular electron transfer is eliminated once the donor amino group next to the chromophore is protonated. The utility of these molecules for phototherapy of cancer is confirmed by the drastic increase in toxicity of five conjugates against cancer cell lines upon photoactivation.

    摘要翻译： 光活化赖氨酸缀合物的双链DNA切割的化合物和方法在适于通过存在不同碱性的两个氨基的癌细胞的选择性靶向的微酸性pH下得到增强。 第一个氨基起增强对DNA的溶解度和亲和力的辅助作用，而位于光激活的DNA切割器旁边的第二个氨基在期望的pH阈值下进行质子化。 质子化导致两个协同作用，这说明在较低的pH值下增加的DNA切割能力：在较低pH下更紧密地结合DNA; 一旦发色团旁边的供体氨基被质子化，就消除了通过分子内电子转移而猝灭光致变色器的激发态的非生产途径。 这些分子用于癌症光疗的效用通过光活化后五种缀合物对癌细胞系的毒性急剧增加来证实。