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    • 10. 发明申请
    • PEPTIDE MIMETIC LIGANDS OF POLO-LIKE KINASE 1 POLO BOX DOMAIN AND METHODS OF USE
    • POLO-like激素的肽类化合物1 POLO BOX域及其使用方法
    • US20140142044A1
    • 2014-05-22
    • US14111540
    • 2012-04-12
    • Terrence R. Burke, JR.Wenjian QianFa LiuKyung S. LeeJung-Eun Park
    • Terrence R. Burke, JR.Wenjian QianFa LiuKyung S. LeeJung-Eun Park
    • C07K7/06
    • C07K7/06A61K38/00A61K47/60C07K1/006C07K5/0827C12N9/12C12Y207/11021
    • Novel compounds are provided that bind to polo-like kinases through the polo-box domain. In certain embodiments, the novel compounds are PEGylated peptides. The PEGylated peptides in accordance with the invention demonstrate high PBD-binding affinity. In certain embodiments, the PEGylated peptides have also achieved activities in whole cell systems. The invention also provides compounds that bind polo-like kinases through the polo-box domain and possess reduced anionic charge. Further provided are methods of design and/or synthesis of the PEGylated peptides and methods of use thereof. The invention provides methods of use of the compounds and methods of synthesis of the compounds. The compounds of the invention have potential therapeutic activity in view of their binding and inhibitory activities towards Plk1. They are based on the amino acid sequence PLHSpT (phosphorylated Thr). The PEG moiety, when present, is covalently attached at the N-terminus. The invention also encompasses derivatives having substituents on the Pro and/or the His side chains, substituents on the phosphate group, the replacement of His with Gln, the replacement of Pro with a N-substituted Gly, the replacement of Ser with Ala, as well as HS-pT fragments with N-terminal alkoxycarbonyl group and PLHS fragments with a C-terminal glyco-imino-alkylxyalkylamide group.
    • 提供了通过polo-box结构域结合polo样激酶的新型化合物。 在某些实施方案中,新化合物是PEG化肽。 根据本发明的聚乙二醇化肽表现出高PBD结合亲和力。 在某些实施方案中,聚乙二醇化肽还在整个细胞系统中获得活性。 本发明还提供通过马球结构域结合polo样激酶并具有减少的阴离子电荷的化合物。 还提供了聚乙二醇化肽的设计和/或合成方法及其使用方法。 本发明提供了化合物的使用方法和化合物的合成方法。 考虑到它们对Plk1的结合和抑制活性,本发明的化合物具有潜在的治疗活性。 它们基于氨基酸序列PLHSpT(磷酸化的Thr)。 存在时,PEG部分在N末端共价连接。 本发明还包括在Pro和/或His侧链上具有取代基的衍生物,磷酸基团上的取代基,用Gln取代His,用N-取代的Gly取代Pro,用Ala取代Ser,作为 以及具有N-末端烷氧基羰基的HS-pT片段和具有C-末端糖 - 亚氨基 - 烷基烷基酰胺基团的PLHS片段。