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Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation | |
2021-11-05 | |
发表期刊 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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ISSN | 0223-5234 |
卷号 | 223页码:113645 |
发表状态 | 已发表 |
DOI | 10.1016/j.ejmech.2021.113645 |
摘要 |
Protein degradation is a promising strategy for drug development. Proteolysis-targeting chimeras (PROTACs) hijacking the E3 ligase cereblon (CRBN) exhibit enormous potential and universal degradation performance due to the small molecular weight of CRBN ligands. In this study, the CRBN-recruiting PROTACs were explored on the degradation of oncogenic fusion protein BCR-ABL, which drives the pathogenesis of chronic myeloid leukemia (CML). A series of novel PROTACs were synthesized by conjugating BCR-ABL inhibitor dasatinib to the CRBN ligand including pomalidomide and lenalidomide, and the extensive structure-activity relationship (SAR) studies were performed focusing on optimization of linker parameters. Therein, we uncovered that pomalidomide-based degrader 17 (SIAIS056), possessing sulfur-substituted carbon chain linker, exhibits the most potent degradative activity in vitro and favorable pharmacokinetics in vivo. Besides, degrader 17 also degrades a variety of clinically relevant resistance-conferring mutations of BCR-ABL. Furthermore, degrader 17 induces significant tumor regression against K562 xenograft tumors. Our study indicates that 17 as an efficacious BCR-ABL degrader warrants intensive investigation for the future treatment of BCR-ABL+ leukemia. |
关键词 | PROTAC,CRBN,Leukemia,BCR-ABL ,Degradation |
收录类别 | SCI ; SCIE ; IC |
语种 | 英语 |
WOS研究方向 | Pharmacology & Pharmacy |
WOS类目 | Chemistry, Medicinal |
WOS记录号 | WOS:000695696100026 |
出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
原始文献类型 | Article |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/128133 |
专题 | 生命科学与技术学院_博士生 免疫化学研究所_特聘教授组_生物工程学实验室 免疫化学研究所_特聘教授组_抗体化学实验室 科技发展处 生命科学与技术学院_硕士生 物质科学与技术学院_博士生 |
共同第一作者 | Ding XY(丁欣雨); Liu LY(刘林义) |
通讯作者 | Yang XB(杨小宝); Yin QQ(阴倩倩); Jiang B(姜标) |
作者单位 | 1.Shanghai Institute for Advanced Immunochemical Studies, China 2.School of Life Science and Technology, China 3.School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China 4.Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, School of Pharmaceutical Science, University of South China, Hengyang City, 421001, China 5.University of Chinese Academy of Sciences, Beijing, 100049, China 6.Department of Histology and Embryology, Anhui Medical University, Hefei, 230032, China 7.CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China |
第一作者单位 | 物质科学与技术学院 |
推荐引用方式 GB/T 7714 | Liu HX,Ding XY,Liu LY,et al. Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,223:113645. |
APA | Liu HX.,Ding XY.,Liu LY.,Mi QL.,Zhao QJ.,...&Jiang B.(2021).Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,223,113645. |
MLA | Liu HX,et al."Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 223(2021):113645. |
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