基于ZAc热点区域的BRD4 Bromodomain抑制剂设计与活性研究

doi:10.5246/jcps.2023.12.078

中国药学(英文版) ›› 2023, Vol. 32 ›› Issue (12): 971-988.DOI: 10.5246/jcps.2023.12.078

基于ZAc热点区域的BRD4 Bromodomain抑制剂设计与活性研究

李慧丽¹^,², 李珏¹, 何丹丹¹, 陶玲¹, 江渝斌¹, 沈祥春¹^,²^,^*(), 姜飞¹^,²^,^*()

1. 贵州医科大学省部共建药用植物功效与利用国家重点实验室, 贵州贵阳 550025
2. 贵州医科大学药学院天然药物资源优效利用重点实验室, 贵州贵阳 550025

收稿日期:2023-04-10 修回日期:2023-05-21 接受日期:2023-06-19 出版日期:2024-01-04 发布日期:2023-12-31
通讯作者: 沈祥春, 姜飞
作者简介:
+ Tel.: +86-851-88416153, E-mail: shenxiangchun@126.com
+ E-mail: jonesfrede@126.com
基金资助:
Guizhou Province Ordinary Colleges and Universities Youth Science and Technology Talent Growth Project (Grant No. QJH-KY[2022]249, QJH-KY[2022]250), Science and Technology Fund of Guizhou Provincial Health Commission (Grant No. GZWKJ2022-464 and GZWKJ2022-466), the Basic Research Program of Guizhou Province, Guizhou Provience Science and Technology Foundation, China (Grant No. QKHJC-ZK[2021]YB553, QKHRCZK[2023]YB308, and QKHJC-ZK[2023]ZD035), Cultivation Project of National Natural Science Foundation of Guizhou Medical University (Grant No. 20NSP052), The Start-up Foundation for Doctors of Guizhou Medical University (Grant No. YJ2020-BK035), Provincial College Student Innovation, Entrepreneurship Training Program (Grant No. S202010660142), the Guizhou Provincial Scientific and Technologic Innovation Base (Grant No. [2023]003) and the National Natural Science Foundation of China (Grant No. 22307026).

Design and evaluation of potent BRD4 Bromodomain inhibitors based on ZA channel hot spot

Huili Li¹^,², Jue Li¹, Dandan He¹, Ling Tao¹, Yubing Jiang¹, Xiangchun Shen¹^,²^,^*(), Fei Jiang¹^,²^,^*()

1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, Guizhou, China
2 The Key Laboratory of Optimal Utilization of Natural Medicine Resources, Guizhou Medical University, Guiyang 550025, Guizhou, China

Received:2023-04-10 Revised:2023-05-21 Accepted:2023-06-19 Online:2024-01-04 Published:2023-12-31
Contact: Xiangchun Shen, Fei Jiang

摘要/Abstract

摘要：

Bromodomain是一种表观遗传读取器, 在识别乙酰化组蛋白方面发挥关键功能而越来越受到关注。Bromodomain结构域的蛋白质与多种疾病的发展有关, 靶向Bromodomain结构域已成为开发蛋白质-蛋白质相互作用抑制剂的重要策略。本研究在BRD4的乙酰赖氨酸结合位点中发现了ZA通道上的新热点。为探究该热点的重要性, 对基于结构的3,5-二甲基异恶唑基BRD4抑制剂(4)进行了药物设计, 并围绕ZA通道热点合成了一系列具有结构修饰的衍生物。结构优化产生了具有纳摩尔蛋白和细胞效力的有前途的衍生物21。研究表明, ZA通道热点可能在BRD4抑制剂的活性和选择性中起重要作用。

关键词: 蛋白-蛋白相互作用, BRD4, ZAc区域, 急性髓性白血病细胞

Abstract:

Bromodomain, an epigenetic reader module, is garnering increasing interest due to its critical function in recognizing acetylated histones. Bromodomain-containing proteins have been implicated in the development of various diseases, making the targeting of bromodomain a significant strategy for developing protein-protein interaction (PPI) inhibitors. In the present study, a novel hot spot was identified on the ZA channel, which is located in the acetyl lysine binding site of BRD4. To investigate the significance of this hot spot, structure-based drug design was conducted on a 3,5-dimethylisoxazole-based BRD4 inhibitor (4). A series of derivatives were synthesized with structural modifications focusing on the ZA channel hot spot. Through structural optimization, a promising derivative compound 21, was developed, demonstrating nanomolar protein and cell potency. This study suggested that the ZA channel hot spot might play a crucial role in the activity and selectivity of BRD4 inhibitors.

Key words: Protein-protein interactions, BRD4, ZA Channel, Acute myeloid leukemia cell

Supporting:

李慧丽, 李珏, 何丹丹, 陶玲, 江渝斌, 沈祥春, 姜飞. 基于ZAc热点区域的BRD4 Bromodomain抑制剂设计与活性研究[J]. 中国药学(英文版), 2023, 32(12): 971-988.

Huili Li, Jue Li, Dandan He, Ling Tao, Yubing Jiang, Xiangchun Shen, Fei Jiang. Design and evaluation of potent BRD4 Bromodomain inhibitors based on ZA channel hot spot[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(12): 971-988.

图/表 11

Table 1. IC50 and Ki values of compounds 9–24 against BRD4(1) and BRD4(2) using FP assay, respectively (mean ± SD, n = 3).

Table 2. The percentage inhibition of compounds 25–27 against diverse BRDs under 25 μM (mean ± SD, n = 3).

Table 3. Effect of compounds 18, 21, and 24 in cancer cell lines (n = 3).

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基于ZAc热点区域的BRD4 Bromodomain抑制剂设计与活性研究

Design and evaluation of potent BRD4 Bromodomain inhibitors based on ZA channel hot spot

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