Design and Synthesis of Novel Bispecific Molecules for Inducing BRD4 Protein Degradation

作     者：WANG Shihui SONG Yuming WANG Yue GAO Yang YU Shanshan ZHAO Qianqian JIN Xiangqun LU Haibin 

作者机构：College of Pharmacy Jilin University Changehun 130021 P. R. China China-Japan Union Hospital of Jilin University Changchun 130033 P. R. China 

基　　金：Supported by the Science and Technology Development Plan Projects of Jilin Province  China 

出 版 物：《Chemical Research in Chinese Universities》 (高等学校化学研究（英文版）)

年 卷 期：2018年第34卷第1期

页      码：67-74页

摘      要：Proteolysis targeting chimeras（PROTACs） are bispecific molecules containing a target protein binder and a ubiquitin ligase binder connected by a linker. Recently, some heterobifunctional small molecule bromodomain-containing protein 4（BRD4） degraders based on the concept of PROTACs were designed to induce the degradation of BRD4 protein. Herein, we synthesized a new class of PROTAC BRD4 degraders. One of the most promising compound 22f exhibited robust potency of BRD4 inhibition with IC50 value of （9.4±0.6） nmol/L. Furthermore, com- pound 22f potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC50 value of （27.6±1.6） nmol/L and capable of inducing degradation of BRD4 protein at 0.5-1.0 μmol/L in the RS4;11 cells. These data establish that compound 22f is a potent and efficacious BRD4 degrader.

主 题 词：Proteolysis targeting chimera(PROTAC) Bromodomam-containing protein 4(BR/M) degrader Bromodomain-containing protein 4(BRD4) inhibitor 

学科分类：0710[理学-生物科学类] 071010[071010] 081704[081704] 07[理学] 08[工学] 0817[工学-轻工类] 070305[070305] 080501[080501] 0805[工学-能源动力学] 0703[理学-化学类] 

核心收录：

D　O　I：10.1007/S40242-018-7272-5

馆 藏 号：203284366...