Design and Synthesis of Proteolysis Targeting Chimeras for Inducing BRD4 Protein Degradation

doi:10.1007/s40242-018-7299-7

高等学校化学研究 ›› 2018, Vol. 34 ›› Issue (2): 221-228.doi: 10.1007/s40242-018-7299-7

Design and Synthesis of Proteolysis Targeting Chimeras for Inducing BRD4 Protein Degradation

WANG Shihui¹, LI Haiyan², WANG Yue¹, GAO Yang¹, YU Shanshan¹, ZHAO Qianqian¹, JIN Xiangqun¹, LU Haibin¹

1. College of Pharmacy, Jilin University, Changchun 130021, P. R. China;
2. Affiliated Hospital of Changchun University of Chinese Medicine, Changchun 130021, P. R. China

收稿日期:2017-09-07 修回日期:2018-01-08 出版日期:2018-04-01 发布日期:2013-05-15
通讯作者: JIN Xiangqun,E-mail:jingxq@jlu.edu.cn;LU Haibin,E-mail:haibin1025@163.com E-mail:jingxq@jlu.edu.cn;haibin1025@163.com
基金资助:
Supported by the Science and Technology Development Plan Projects of Jilin Province, China(No.20170311057YY).

Design and Synthesis of Proteolysis Targeting Chimeras for Inducing BRD4 Protein Degradation

WANG Shihui¹, LI Haiyan², WANG Yue¹, GAO Yang¹, YU Shanshan¹, ZHAO Qianqian¹, JIN Xiangqun¹, LU Haibin¹

1. College of Pharmacy, Jilin University, Changchun 130021, P. R. China;
2. Affiliated Hospital of Changchun University of Chinese Medicine, Changchun 130021, P. R. China

Received:2017-09-07 Revised:2018-01-08 Online:2018-04-01 Published:2013-05-15
Contact: JIN Xiangqun,E-mail:jingxq@jlu.edu.cn;LU Haibin,E-mail:haibin1025@163.com E-mail:jingxq@jlu.edu.cn;haibin1025@163.com
Supported by:
Supported by the Science and Technology Development Plan Projects of Jilin Province, China(No.20170311057YY).

摘要/Abstract

摘要： In this paper, we synthesized a series of proteolysis targeting chimeras(PROTACs) using VHL E3 ligase ligands for BRD4 protein degradation. One of the most promising compound 19g exhibited robust potency of BRD4 inhibition with IC₅₀ value of (18.6±1.3) nmol/L, respectively. Furthermore, compound 19g potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC₅₀ value of (34.2±4.3) nmol/L and capable of inducing degradation of BRD4 protein at 0.4—0.6 µmol/L in the RS4;11 leukemia cells. These data show that compound 19g is a highly potent and efficacious BRD4 degrader.

关键词: Proteolysis targeting chimera(PROTAC), BRD4 degrader, VHL ligand

Abstract: In this paper, we synthesized a series of proteolysis targeting chimeras(PROTACs) using VHL E3 ligase ligands for BRD4 protein degradation. One of the most promising compound 19g exhibited robust potency of BRD4 inhibition with IC₅₀ value of (18.6±1.3) nmol/L, respectively. Furthermore, compound 19g potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC₅₀ value of (34.2±4.3) nmol/L and capable of inducing degradation of BRD4 protein at 0.4—0.6 µmol/L in the RS4;11 leukemia cells. These data show that compound 19g is a highly potent and efficacious BRD4 degrader.

Key words: Proteolysis targeting chimera(PROTAC), BRD4 degrader, VHL ligand

WANG Shihui, LI Haiyan, WANG Yue, GAO Yang, YU Shanshan, ZHAO Qianqian, JIN Xiangqun, LU Haibin. Design and Synthesis of Proteolysis Targeting Chimeras for Inducing BRD4 Protein Degradation[J]. 高等学校化学研究, 2018, 34(2): 221-228.

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Design and Synthesis of Proteolysis Targeting Chimeras for Inducing BRD4 Protein Degradation

Design and Synthesis of Proteolysis Targeting Chimeras for Inducing BRD4 Protein Degradation

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