2. Academic Validation
  3. Adjusted degradation of BRD4 S and BRD4 L based on fine structural modifications of the pyrrolopyridone scaffold

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

  • Eur J Med Chem. 2022 Jun 5;236:114259. 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 8,  Youhong Hu 9
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, 1 Xiangshanzhi Road, Hangzhou, 310024, China.
  • 2 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.
  • 3 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.
  • 4 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.
  • 5 College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, 310053, China.
  • 6 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.
  • 7 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.
  • 8 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. Electronic address: [email protected].
  • 9 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. Electronic address: [email protected].
PMID: 35395439 DOI: 10.1016/j.ejmech.2022.114259
Abstract

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.

Keywords

BRD4 S; PROTAC; Pyrrolopyridone; Selectivity.

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