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

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

doi:10.1016/j.ejmech.2022.114259

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. Epub 2022 Mar 31.

Authors

Jingjing Chen¹, Huixin He², Aihuan Wei³, Yalei Li⁴, Gang Cheng⁵, Hui Qin⁶, Hanyue Zhong⁶, Hongchun Liu⁴, Meiyu Geng⁷, Aijun Shen⁸, Youhong Hu⁹

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: shenaj@simm.ac.cn.
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: yhhu@simm.ac.cn.

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.

MeSH terms

Antineoplastic Agents* / pharmacology
Cell Cycle Proteins
Nuclear Proteins* / metabolism
Structure-Activity Relationship
Transcription Factors / metabolism

Substances

Antineoplastic Agents
Cell Cycle Proteins
Nuclear Proteins
Transcription Factors