Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (4): 1712-1721.DOI: 10.6023/cjoc202007059 Previous Articles     Next Articles


基于ABBV-075的新型溴结构域蛋白4 (BRD4)小分子抑制剂的设计、合成及活性评价

徐晨淏a,b,c,d, 龚云鹏a,b,c,d, 陈雅欣a,b,c,d, 宋启梦a,b,c,d, 李娇a,b,c,d, 郑一超a,b,c,d, 李雯a,b,c,d,*(), 孙凯a,b,c,d,*(), 刘宏民a,b,c,d,*()   

  1. a 郑州大学药学院 郑州 450001
    b 郑州大学药物研究院 郑州 450001
    c 新药创制与药物安全性评价河南省协同创新中心 郑州 450001
    d 药物关键制备技术教育部重点实验室 郑州 450001
  • 收稿日期:2020-07-26 修回日期:2020-10-21 发布日期:2020-12-05
  • 通讯作者: 李雯, 孙凯, 刘宏民
  • 基金资助:
    国家自然科学基金(81438005); 国家自然科学基金(81773562); 国家蛋白质重点研究项目基金(SQ2018YFE011359); 河南省重点研究项目基金(1611003110100)

Design, Synthesis and Activity Evaluation of Novel Bromodomain-Containing Protein 4 (BRD4) Small Molecule Inhibitor Based on ABBV-075

Chenhao Xua,b,c,d, Yunpeng Gonga,b,c,d, Yaxin Chena,b,c,d, Qimeng Songa,b,c,d, Jiao Lia,b,c,d, Yichao Zhenga,b,c,d, Wen Lia,b,c,d,*(), Kai Suna,b,c,d,*(), Hongmin Liua,b,c,d,*()   

  1. a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
    b Institute of Drug Discovery & Development, Zhengzhou University, Zhengzhou 450001
    c Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001
    d Key Laboratory of Technology of Drug Preparation, Ministry of Education, Zhengzhou 450001
  • Received:2020-07-26 Revised:2020-10-21 Published:2020-12-05
  • Contact: Wen Li, Kai Sun, Hongmin Liu
  • About author:
    * Corresponding authors. E-mail: ;
  • Supported by:
    National Natural Science Foundation of China(81438005); National Natural Science Foundation of China(81773562); National Key Research Program of Proteins(SQ2018YFE011359); Key Research Program of Henan Province(1611003110100)

In order to discover novel bromodomain-containing protein 4 (BRD4) small molecule inhibitor, 16 compounds with 4 different nuclei based on ABBV-075 were designed and synthesized through scaffold hopping. The conditions of the Suzuki coupling reaction in the synthesis steps were optimized and the activity of all compounds against BRD4 was tested. The results indicated that compound N-(4-(2,4-difluorophenoxy)-3-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)- phenyl)ethanesulfonamide (15o) had 51% at concentration of 10 μmol/L with IC 50 value of (16.39±1.20) μmol/L, possessing obvious BRD4 inhibitory activity. The molecular docking results showed that15oformed key hydrogen bonds with Asn433 and Asp381. The picture of superposed conformation of 15o and homolog of ABBV-075 exhibited the combination difference between them, explaining the reason of activity gap, which would provide excellent ideas for further study.

Key words: BRD4 inhibitor, ABBV-075, synthesis and optimization, bioactivity, molecular docking