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Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines

文献类型：期刊论文

作者Yan, Ziqin1; Lyu, Xilin1; Lin, Dongze3; Wu, Gaoxing1,2; Gong, Yang1,5; Ren, Xuelian4; Xiao, Jian2,3; Lou, Jianfeng1,2; Huang, He2,4; Chen, Yi3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-06-05
卷号254页码:17
ISSN号0223-5234
DOI10.1016/j.ejmech.2023.115381
通讯作者Chen, Yi(ychen@simm.ac.cn) ; Zhao, Yujun(yjzhao@simm.ac.cn)
英文摘要Targeted degradation of BET family proteins BRD2/3/4 or only BRD4 with PROTAC molecules has been a promising strategy for the treatment of human cancer. Meanwhile, selective degradation of cellular BRD3 and BRD4-L remains a challenging task. We report herein a novel PROTAC molecule 24 that promoted selective degradation of cellular BRD3 and BRD4-L, but not BRD2 or BRD4-S, in a panel of six cancer cell lines. The observed target selectivity was partially attributed to differences in protein degradation kinetics and in types of cell lines. In a MM.1S mouse xenograft model, an optimized lead compound 28 promoted selective degradation of BRD3 and BRD4-L in vivo and exhibited robust antitumor activity. In summary, we have demonstrated that selective degradation of BRD3 and BRD4-L over BRD2 and BRD4-S is a feasible and robust approach in multiple cancer cell lines and an animal model, which could be helpful for further investigations on BRD3 and BRD4-L that ultimately benefitting cancer research and therapeutics.
WOS关键词INDUCED PROTEIN-DEGRADATION ; E3 UBIQUITIN LIGASE ; DRUG DISCOVERY ; BROMODOMAIN ; POTENT ; INHIBITOR ; DEGRADER ; CONJUGATION ; DESIGN
资助项目National Natural Science Foundation of China[82073682] ; National Natural Science Foundation of China[81872724] ; National Natural Science Foundation of China[82273759] ; National Natural Science Foundation of China[81973164] ; National Natural Science Foundation of China[81673295] ; Jinan Innovation Team Project[2021GXRC069] ; Shanghai Municipal Science and Technology Major Project, and Science and Technology Commission of Shanghai Municipality[22ZR1474500] ; Shanghai Municipal Science and Technology Major Project, and Science and Technology Commission of Shanghai Municipality[18431907100]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:000990637100001
源URL[http://119.78.100.183/handle/2S10ELR8/306653]  
专题新药研究国家重点实验室
通讯作者Chen, Yi; Zhao, Yujun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res & Small Mol Drug Res Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
6.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China
7.Shandong Acad Pharmaceut Sci, Shandong Prov Key Lab Biopharmaceut, Jinan 250101, Peoples R China
推荐引用方式
GB/T 7714		 Yan, Ziqin,Lyu, Xilin,Lin, Dongze,et al. Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,254:17.
APA Yan, Ziqin.,Lyu, Xilin.,Lin, Dongze.,Wu, Gaoxing.,Gong, Yang.,...&Zhao, Yujun.(2023).Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,254,17.
MLA Yan, Ziqin,et al."Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 254(2023):17.

入库方式： OAI收割

来源：上海药物研究所

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