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Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-10 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00635 Andrew P. Crew 1 , Kanak Raina 1 , Hanqing Dong 1 , Yimin Qian 1 , Jing Wang 1 , Dominico Vigil 1 , Yevgeniy V. Serebrenik , Brian D. Hamman 1 , Alicia Morgan 1 , Caterina Ferraro 1 , Kam Siu 1 , Taavi K. Neklesa 1 , James D. Winkler 1 , Kevin G. Coleman 1 , Craig M. Crews
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-10 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00635 Andrew P. Crew 1 , Kanak Raina 1 , Hanqing Dong 1 , Yimin Qian 1 , Jing Wang 1 , Dominico Vigil 1 , Yevgeniy V. Serebrenik , Brian D. Hamman 1 , Alicia Morgan 1 , Caterina Ferraro 1 , Kam Siu 1 , Taavi K. Neklesa 1 , James D. Winkler 1 , Kevin G. Coleman 1 , Craig M. Crews
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Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that recruit an E3 ligase to a target protein to facilitate ubiquitination and subsequent degradation of that protein. While the field of targeted degraders is still relatively young, the potential for this modality to become a differentiated and therapeutic reality is strong, such that both academic and pharmaceutical institutions are now entering this interesting area of research. In this article, we describe a broadly applicable process for identifying degrader hits based on the serine/threonine kinase TANK-binding kinase 1 (TBK1) and have generalized the key structural elements associated with degradation activities. Compound 3i is a potent hit (TBK1 DC50 = 12 nM, Dmax = 96%) with excellent selectivity against a related kinase IKKε, which was further used as a chemical tool to assess TBK1 as a target in mutant K-Ras cancer cells.
中文翻译：
TANK结合激酶1的靶向靶向嵌合体（Von Hippel-Lindau-Recruiting蛋白水解）的鉴定和表征。
靶向嵌合体的蛋白水解（PROTAC）是双功能分子，可将E3连接酶募集至目标蛋白质，以促进该蛋白质的泛素化和随后的降解。虽然靶向降解剂的领域还比较年轻，但这种方法成为分化和治疗现实的潜力很强，因此学术机构和制药机构现在都在进入这一有趣的研究领域。在本文中，我们描述了一种基于丝氨酸/苏氨酸激酶TANK结合激酶1（TBK1）识别降解子命中点的广泛适用的过程，并概括了与降解活动相关的关键结构要素。化合物3i命中率很高（TBK1 DC 50 = 12 nM，D max （= 96％）对相关激酶IKKε具有优异的选择性，该激酶还被用作化学工具，以评估TBK1作为突变K-Ras癌细胞中的靶标。
更新日期：2017-07-10
中文翻译：
TANK结合激酶1的靶向靶向嵌合体（Von Hippel-Lindau-Recruiting蛋白水解）的鉴定和表征。
靶向嵌合体的蛋白水解（PROTAC）是双功能分子，可将E3连接酶募集至目标蛋白质，以促进该蛋白质的泛素化和随后的降解。虽然靶向降解剂的领域还比较年轻，但这种方法成为分化和治疗现实的潜力很强，因此学术机构和制药机构现在都在进入这一有趣的研究领域。在本文中，我们描述了一种基于丝氨酸/苏氨酸激酶TANK结合激酶1（TBK1）识别降解子命中点的广泛适用的过程，并概括了与降解活动相关的关键结构要素。化合物3i命中率很高（TBK1 DC 50 = 12 nM，D max （= 96％）对相关激酶IKKε具有优异的选择性，该激酶还被用作化学工具，以评估TBK1作为突变K-Ras癌细胞中的靶标。
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