Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML
Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML
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DOI：
10.1016/j.chembiol.2018.11.006
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发表时间：
2019-02-21
影响因子：
8.6
通讯作者：
Winter, Georg E.
中科院分区：
文献类型：
--
作者：
Brand, Matthias;Jiang, Baishan;Winter, Georg E.
选择性小分子的设计经常受到类似配体结合口袋的阻碍。在这里，我们报告了BSJ-03-123，一种基于邻苯二甲酰亚胺的降解剂，利用蛋白质界面决定簇来实现对细胞周期蛋白依赖性激酶6（CDK 6）降解的蛋白质组范围的选择性。药理学CDK 6降解靶向急性髓性白血病细胞的选择性依赖性，并且CDK 6的急性降解的转录组学和磷酸蛋白质组学分析使得能够动态映射其在协调信号传导和转录中的直接作用。
The design of selective small molecules is often stymied by similar ligand binding pockets. Here, we report BSJ-03-123, a phthalimide-based degrader that exploits protein-interface determinants to achieve proteome-wide selectivity for the degradation of cyclin-dependent kinase 6 (CDK6). Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and transcriptomics and phosphoproteomics profiling of acute degradation of CDK6 enabled dynamic mapping of its immediate role in coordinating signaling and transcription.