Lu Haibo, Lu Tian, Zu Shijia, Duan Zhe, Guang Yiman, Li Qi, Ma Jingyi, Chen Dongying, Li Bo, Lu Wenchao, Jiang Hualiang, Luo Cheng, Ye Deyong, Chen Kaixian, Lin Hua
School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; GuiZhou University of Traditional Chinese Medicine, Guizhou 550025, China.
Bioorg Chem. 2022 Jun;123:105768. doi: 10.1016/j.bioorg.2022.105768. Epub 2022 Mar 26.
Cat eye syndrome chromosome region candidate 2 (CECR2) bromodomain is a module of CECR2-containing remodeling factor (CERF), which is a chromatin remodeling complex correlating with transcriptional control and adjustment of chromatin architecture. Potent chemical probes would be beneficial to gain insights into the biochemical and pharmacological functions of CECR2 BRD. Herein, we report the discovery of a series of CECR2 BRD inhibitors with 7H-pyrrolo[2,3-d] pyrimidine scaffold based on molecular docking model of TP-248 and CECR2 BRD. The most potent inhibitor of this series, DC-CBi-22 with IC of 8.0 ± 1.4 nM against CECR2 BRD and selectivity over BPTF BRD up to 24.9-fold. The SARs were detailed according to molecular docking. DC-CBi-22 would serve as a useful chemical probe for the study of CECR2.
猫眼综合征染色体区域候选基因2（CECR2）的溴结构域是含CECR2重塑因子（CERF）的一个模块，CERF是一种与转录调控及染色质结构调整相关的染色质重塑复合体。有效的化学探针将有助于深入了解CECR2溴结构域的生化和药理功能。在此，我们基于TP-248与CECR2溴结构域的分子对接模型，报告了一系列具有7H-吡咯并[2,3-d]嘧啶骨架的CECR2溴结构域抑制剂的发现。该系列中最有效的抑制剂DC-CBi-22对CECR2溴结构域的IC50为8.0±1.4 nM，对BPTF溴结构域的选择性高达24.9倍。根据分子对接详细阐述了构效关系。DC-CBi-22将作为研究CECR2的有用化学探针。
