Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF.
Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF.
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DOI：
10.1021/acs.jmedchem.5b00458
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发表时间：
2016-02-25
影响因子：
7.3
通讯作者：
Knapp S
中科院分区：
文献类型：
--
作者：
Bennett J;Fedorov O;Tallant C;Monteiro O;Meier J;Gamble V;Savitsky P;Nunez-Alonso GA;Haendler B;Rogers C;Brennan PE;Müller S;Knapp S
TRIM24是一种转录调节因子，也是E3泛素连接酶。它在多种肿瘤中过表达，高表达水平与乳腺癌患者预后不良有关。TRIM24包含一个PHD/bromodomain，为开发针对该蛋白质相互作用模块的蛋白质相互作用抑制剂提供了机会。在这里，我们发现了有效的乙酰赖氨酸模拟苯并咪唑酮TRIM24溴结构域抑制剂。该系列的最佳化合物是选择性BRPF1B/TRIM24双抑制剂，其结合KD分别为137 nM和222 nM，但对其他溴域具有良好的选择性。使用FRAP测定和细胞活力数据证明了抑制剂的细胞活性。
TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumors, and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD/bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/TRIM24 dual inhibitor that bound with a KD of 137 and 222 nM, respectively, but exerted good selectivity over other bromodomains. Cellular activity of the inhibitor was demonstrated using FRAP assays as well as cell viability data.