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1. 发明申请

WO2012078559A3 SMALL-MOLECULE HYDROPHOBIC TAGGING OF FUSION PROTEINS AND INDUCED DEGRADATION OF SAME 审中-公开
标题翻译：融合蛋白的小分子疏水标记及其诱导降解
公开(公告)号：WO2012078559A3
公开(公告)日：2012-12-06
申请号：PCT/US2011063401
申请日：2011-12-06
申请人： UNIV YALE , CREWS CRAIG M , TAE HYUN SEOP , SCHNEEKLOTH ASHLEY R , NEKLESA TAAVI , SUNDBERG THOMAS
发明人： CREWS CRAIG M , TAE HYUN SEOP , SCHNEEKLOTH ASHLEY R , NEKLESA TAAVI , SUNDBERG THOMAS
IPC分类号： C07K17/02 , A61K31/66 , A61K31/7076 , A61K31/708 , A61P31/00
CPC分类号： G01N33/573 , A61K47/48015 , A61K47/52 , C07K1/13 , C07K2319/20 , C07K2319/95 , C12N9/14 , G01N33/5008 , G01N2500/10
摘要： The present invention relates to the ability to regulate any protein of interest in living systems with small molecules. In particular, the present invention relates to the discovery that appending a hydrophobic moiety to the surface of a protein can mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation. An aspect of the present invention relates to bifunctional small molecules that bind a number of proteins, including, for example, a self-labeling tag such as bacterial dehalogenase (HaloTag protein) and present a hydrophobic group on its surface. Hydrophobic tagging of the HaloTag protein with a hydrophobic moiety (e.g. an adamantyl moiety) was effected and the tagging induced the degradation of cytosolic, isoprenylated, and transmembrane fusion proteins in cell culture. The present invention also demonstrated the in vivo utility of hydrophobic tagging by degrading proteins expressed in zebrafish embryos and by inhibiting RasG12V-driven tumor progression in mice. Therefore, hydrophobic tagging of HaloTag fusion proteins affords small molecule control over any protein of interest, making it an ideal system for validating potential drug targets in disease models.
摘要翻译：本发明涉及用小分子调节活体系中感兴趣的任何蛋白质的能力。特别地，本发明涉及这样的发现，即将疏水部分附加到蛋白质的表面上可以模拟蛋白质的部分变性状态，从而使细胞质量控制机构引起其蛋白酶体降解。本发明的一个方面涉及结合许多蛋白质的双功能小分子，包括例如自标记标签如细菌脱卤素酶（HaloTag蛋白质）并且在其表面上呈现疏水基团。用疏水部分（例如金刚烷基部分）对HaloTag蛋白质进行疏水性标记，标记诱导细胞培养物中胞质，异丙基化和跨膜融合蛋白质的降解。本发明还通过降解在斑马鱼胚胎中表达的蛋白质和通过抑制小鼠中RasG12V驱动的肿瘤进展来证明疏水性标签的体内实用性。因此，HaloTag融合蛋白的疏水标签可以使小分子控制任何感兴趣的蛋白质，使其成为验证疾病模型中潜在药物靶点的理想系统。

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