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

doi:10.1007/s40242-018-7299-7

Chemical Research in Chinese Universities ›› 2018, Vol. 34 ›› Issue (2): 221-228.doi: 10.1007/s40242-018-7299-7

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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).

Abstract

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]. Chemical Research in Chinese Universities, 2018, 34(2): 221-228.

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

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