2. Academic Validation
  3. Design, synthesis, and biological evaluation of KDM5B degraders against hematologic malignancy cells

Design, synthesis, and biological evaluation of KDM5B degraders against hematologic malignancy cells

  • Eur J Med Chem. 2025 Oct 15:296:117883. doi: 10.1016/j.ejmech.2025.117883.
Xiaowen Liu 1,  Jiarong Li 2,  Yihao Guo 3,  Zhicheng Xie 4,  Meiyu Geng 5,  Youhong Hu 6,  Aijun Shen 7,  Zhuo Zhang 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
  • 3 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
  • 5 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
  • 6 School of Pharmacy, Henan University, Kaifeng, Henan, 475004, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; State Key Laboratory of Drug Research, 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, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, 1 Xiangshanzhi Road, Hangzhou, 310024, China. Electronic address: yhhu@simm.ac.cn.
  • 7 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Lingang Laboratory, Shanghai, 200031, China. Electronic address: shenaj@simm.ac.cn.
  • 8 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China. Electronic address: s18-zhangzhuo@simm.ac.cn.
PMID: 40578256 DOI: 10.1016/j.ejmech.2025.117883
Abstract

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.

Keywords

Hematological malignancy; KDM5B; PROTAC; TPD.

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