Discovery of novel small molecule induced selective degradation of the bromodomain and extra-terminal (BET) bromodomain protein BRD4 and BRD2 with cellular potencies
Discovery of novel small molecule induced selective degradation of the bromodomain and extra-terminal (BET) bromodomain protein BRD4 and BRD2 with cellular potencies
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发现具有细胞效力的新型小分子诱导溴结构域和末端外 (BET) 溴结构域蛋白 BRD4 和 BRD2 的选择性降解
DOI：
10.1016/j.bmc.2019.115181
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发表时间：
2020-01-01
影响因子：
3.5
通讯作者：
Chen, Yadong
中科院分区：
文献类型：
--
作者：
Jiang, Fei;Wei, Qingyun;Chen, Yadong
BET 蛋白 BRD2、BRD3 和 BRD4 在转录调节中发挥重要作用，并且可以被 BET 蛋白的蛋白水解靶向嵌合体 (PROTAC) 降解。然而，BET 内蛋白质选择性的缺乏限制了当前降解剂作为靶标验证探针的范围，并可能在治疗环境中导致不良副作用或毒性。我们在此描述了 PROTAC BET 降解剂的设计、合成和评估，该降解剂基于对第一个溴结构域苯并[cd]吲哚-2-酮、烷基酰胺接头和 cereblon 配体沙利度胺具有选择性的 BET 抑制剂。与 BRD3 相比，化合物 15 有效且快速地诱导可逆、持久且出乎意料地选择性去除 BRD4 和 BRD2，这不仅能有效抑制人急性白血病细胞系的细胞生长，而且能非常有效地抑制实体瘤，且在 NCI 60 细胞系的细胞谱中具有低细胞毒性作用。在急性髓系白血病细胞系 MV4-11 中，观察到 BRD4 降解和 c-Myc 驱动的抗增殖活性对接头长度具有显着依赖性。小分子 15 代表了一类新型、有效、选择性的 BRD4 和 BRD2 降解剂，可用于开发治疗癌症的疗法。
The BET proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation and can be degraded by proteolysis-targeting chimeras (PROTACs) for BET proteins. However, the lack of intra-BET proteins selectivity limits the scope of current degraders as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We describe herein the design, synthesis, and evaluation of PROTAC BET degraders, based on the BET inhibitor with selectivity for the first Bromodomain benzo[cd]indole-2-one, alkylamide linker and cereblon ligand thalidomide. Compound 15 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 and BRD2 over BRD3, which not only effectively inhibits cell growth in human acute leukemia cell lines, but also very effective in inhibiting solid tumors with low cytotoxic effect in the cell profiles of NCI 60 cell lines. Remarkable dependency on linker length was observed for BRD4-degrading and c-Myc-driven antiproliferative activities in acute myeloid leukemia cell line MV4-11. The small-molecular 15 represents a novel, potent, and selective class of BRD4 and BRD2 degraders for the development of therapeutics to treat cancers.