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Design, synthesis, and biological evaluation of BRD4 degraders

文献类型：期刊论文

作者Ding, Mengyuan1; Shao, Yingying2; Sun, Danwen2; Meng, Suorina3,4; Zang, Yi3,4,5; Zhou, Yubo2,6; Li, Jia2,5,6; Lu, Wei1,2; Zhu, Shulei1,2
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2023-01-15
卷号78页码:12
关键词PROTAC BRD4 degradation Leukemia Multiple myeloma Pulmonary fibrosis
ISSN号0968-0896
DOI10.1016/j.bmc.2022.117134
通讯作者Li, Jia(jli@simm.ac.cn) ; Lu, Wei(wlu@chem.ecnu.edu.cn) ; Zhu, Shulei(slzhu@chem.ecnu.edu.cn)
英文摘要Epigenetic proteins are one of the important targets in the current research fields of cancer therapy. A family of bromodomain-containing (BRD) and extra terminal domain (BET) proteins act as epigenetic readers to regulate the expression of key oncogenes and anti-apoptotic proteins. Recently, although BET degraders based on PRO-TAC technology have achieved significant antitumor effects, the lack of selectivity for BET protein degradation has not been fully addressed. Herein, a series of small molecule BRD4 PROTACs were designed and synthesized. Most of the degraders were effective in inhibiting MM.1S and MV-4-11 cell lines, especially in MV-4-11. Among them, degrader 8b could induce the degradation of BRD4 and exhibited a time-and concentration-dependent depletion manner and there was a significant depletion of BRD4, laying a foundation for effectively treating leukemia and multiple myeloma. Moreover, 8b could also effectively prevent the activation of MRC5 cells by inducing the degradation of BRD4 protein, which preliminarily proves that the BRD4 degrader based on the PROTAC concept has great potential for the treatment of pulmonary fibrosis. Taken together, these findings laid a foundation for BRD4 degraders as an effective strategy for treating related diseases.
WOS关键词CANCER-THERAPY ; BET INHIBITOR ; BROMODOMAIN ; PROTEINS ; RESISTANCE ; DISCOVERY
资助项目Fundamental Research Funds for the Central Universities ; National Natural Science Foundation of China ; [82104000]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000909014100001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/304061]  
专题新药研究国家重点实验室
通讯作者Li, Jia; Lu, Wei; Zhu, Shulei
作者单位1.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Sch Chem & Mol Engn, Shanghai 200062, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Lingang Lab, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan Tsuihang New Di 528400, Guangdong, Peoples R China
推荐引用方式
GB/T 7714		 Ding, Mengyuan,Shao, Yingying,Sun, Danwen,et al. Design, synthesis, and biological evaluation of BRD4 degraders[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2023,78:12.
APA Ding, Mengyuan.,Shao, Yingying.,Sun, Danwen.,Meng, Suorina.,Zang, Yi.,...&Zhu, Shulei.(2023).Design, synthesis, and biological evaluation of BRD4 degraders.BIOORGANIC & MEDICINAL CHEMISTRY,78,12.
MLA Ding, Mengyuan,et al."Design, synthesis, and biological evaluation of BRD4 degraders".BIOORGANIC & MEDICINAL CHEMISTRY 78(2023):12.

入库方式： OAI收割

来源：上海药物研究所

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