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

Shihui Wang; Haiyan Li; Yue Wang; Yang Gao; Shanshan Yu; Qianqian Zhao; Xiangqun Jin; Haibin Lu

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

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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 de-gradation 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.

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Proteolysis targeting chimera(PROTAC) / BRD4 degrader / VHL ligand

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Shihui Wang, Haiyan Li, Yue Wang, Yang Gao, Shanshan Yu, Qianqian Zhao, Xiangqun Jin, Haibin Lu. Design and Synthesis of Proteolysis Targeting Chimeras for Inducing BRD4 Protein Degradation. Chemical Research in Chinese Universities, 2018, 34(2): 221-228 DOI:10.1007/s40242-018-7299-7

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