当前位置: X-MOL 学术J. Med. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
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
Affiliation  

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
down
wechat
bug