Design, synthesis, and biological evaluation of KDM5B degraders against hematologic malignancy cells
文献类型：期刊论文
| 作者 | Liu, Xiaowen1,2; Li, Jiarong4,5; Guo, Yihao2; Xie, Zhicheng3; Geng, Meiyu2,4,5; Hu, Youhong1,2,3,5,7; Shen, Aijun4,6; Zhang, Zhuo2 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-10-15 |
| 卷号 | 296页码:17 |
| 关键词 | KDM5B PROTAC TPD Hematological malignancy |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2025.117883 |
| 英文摘要 | Histone lysine-specific demethylase 5B (KDM5B) is frequently overexpressed in a wide range of tumors and is regarded as a promising target for drug development. Current drugs targeting KDM5B are primarily small-molecule inhibitors, which suffer from limitations such as poor selectivity and insufficient pharmacological efficacy. Targeted protein degradation (TPD) technology as an emerging drug development strategy has received extensive attention in recent years, that enables the catalytic elimination of the entire protein of interest, thereby disrupting both the enzymatic and non-enzymatic functions. Herein, we investigated a series of novel KDM5B degraders by tethering the KDM5B inhibitor GSK467 to various recruiters that tried to mediate protein degradation via the ubiquitin-proteasome or autophagy-lysosome pathway. Among these, the representative compound YTHu78 effectively induced KDM5B degradation through the ubiquitin-proteasome system and triggered lytic apoptosis in MV-4-11 and MM.1S cell lines. Moreover, YTHu78 demonstrated notable antiproliferative activities against several hematologic malignancy cell lines. In contrast, the KDM5B inhibitor GSK467 neither showed antiproliferative activities in the tested hematologic malignancy cell lines nor induced cell apoptosis. These findings underscore the distinct biological functional differences between the KDM5B degrader and inhibitor. YTHu78 serves as a valuable chemical tool for further exploration of KDM5B's biological roles, and the development of KDM5B-targeted degraders may represent a promising therapeutic strategy for hematologic malignancies in the future. |
| WOS关键词 | LYSINE DEMETHYLASE 5B ; PROLIFERATION ; H3K4ME3 ; JARID1B ; POTENT ; PLU-1 |
| 资助项目 | Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0220232002] ; National Natural Science Foundation of China[82173831] ; Shanghai Municipal Science and Technology Major Project |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001522329300004 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321030]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Hu, Youhong; Shen, Aijun; Zhang, Zhuo |
| 作者单位 | 1.Henan Univ, Sch Pharm, Kaifeng 475004, Henan, Peoples R China 2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 ZuChongZhi Rd, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 5.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 6.Lingang Lab, Shanghai 200031, Peoples R China 7.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, 1 Xiangshanzhi Rd, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu, Xiaowen,Li, Jiarong,Guo, Yihao,et al. Design, synthesis, and biological evaluation of KDM5B degraders against hematologic malignancy cells[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,296:17. |
| APA | Liu, Xiaowen.,Li, Jiarong.,Guo, Yihao.,Xie, Zhicheng.,Geng, Meiyu.,...&Zhang, Zhuo.(2025).Design, synthesis, and biological evaluation of KDM5B degraders against hematologic malignancy cells.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,296,17. |
| MLA | Liu, Xiaowen,et al."Design, synthesis, and biological evaluation of KDM5B degraders against hematologic malignancy cells".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 296(2025):17. |
入库方式： OAI收割
来源：上海药物研究所
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