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Adjusted degradation of BRD4 S and BRD4 L based on fine structural modifications of the pyrrolopyridone scaffold

Eur J Med Chem. 2022-03;

Jingjing Chen, Huixin He, Aihuan Wei, Yalei Li, Gang Cheng, Hui Qin, Hanyue Zhong, Hongchun Liu, Meiyu Geng, Aijun Shen, Youhong Hu

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Proteins, Expression, Isolation and Analysis	… Detection buffer containing XL665-labeled streptavindin and Eu-labeled antibody were … using eBlot L1 wet electrophoretic transfer (GenScript). Blots were blocked with TBST (TBS+0.2…	Get A Quote

摘要

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.