Adjusted degradation of BRD4 S and BRD4 L based on fine structural modifications of the pyrrolopyridone scaffold,European Journal of Medicinal Chemistry

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Adjusted degradation of BRD4 S and BRD4 L based on fine structural modifications of the pyrrolopyridone scaffold
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2022-03-31 , DOI: 10.1016/j.ejmech.2022.114259
Jingjing Chen ₁ , Huixin He ₂ , Aihuan Wei ₃ , Yalei Li ₄ , Gang Cheng ₅ , Hui Qin ₆ , Hanyue Zhong ₆ , Hongchun Liu ₄ , Meiyu Geng ₇ , Aijun Shen ₂ , Youhong Hu ₈

Affiliation

School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, 1 Xiangshanzhi Road, Hangzhou, 310024, China.
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China.
State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China.
College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, 310053, China.
State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, 1 Xiangshanzhi Road, Hangzhou, 310024, China; Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, 1 Xiangshanzhi Road, Hangzhou, 310024, China; State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 110039, China.

Novel pyrrolopyridone BET degraders were designed and synthesized based on the binding mode between the pyrrolopyridone BET inhibitor with the BRD4 protein. The potent degraders on MV-4-11 cells were discovered through structure-activity relationship study. Modification of warhead on pyrrolopyridone BET degraders significantly regulates BRD4 isoform (long and short) protein degradation, which induces differential cell cycle arrest and apoptosis on MV-4-11 cells. Docking study revealed that the fine structural modification of BET degraders may bind with the BD domain of BRD4 protein to engage various surface areas that bind with CRBN.

中文翻译：

基于吡咯并吡啶酮支架的精细结构修饰调整 BRD4 S 和 BRD4 L 的降解

基于吡咯并吡啶酮BET抑制剂与BRD4蛋白的结合方式设计合成了新型吡咯并吡啶酮BET降解剂。通过构效关系研究发现了对MV-4-11细胞的强效降解剂。吡咯并吡啶酮 BET 降解剂上弹头的修饰显着调节 BRD4 同种型（长和短）蛋白降解，从而诱导 MV-4-11 细胞的差异细胞周期停滞和凋亡。对接研究表明，BET 降解剂的精细结构修饰可能与 BRD4 蛋白的 BD 结构域结合，以接合与 CRBN 结合的各种表面区域。

更新日期：2022-03-31

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