2. Academic Validation
  3. Design, synthesis and biological evaluation of WEE1 degraders via HSP90-mediated targeting chimeras for target therapy of acute myeloid leukemia

Design, synthesis and biological evaluation of WEE1 degraders via HSP90-mediated targeting chimeras for target therapy of acute myeloid leukemia

  • Eur J Med Chem. 2025 Jun 5:290:117512. doi: 10.1016/j.ejmech.2025.117512.
Xiaomei Li 1,  Minmin Liu 2,  Huijing Wang 3,  Jialuo Mao 4,  Xiangying Zhai 5,  Tingting He 1,  Jingkun Ma 6,  Yubo Zhou 7,  Wei Lu 1,  Xiaoxuan Yu 8,  Jia Li 9,  Shulei Zhu 10
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, PR China.
  • 2 State Key Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 3 School of Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, PR China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
  • 5 State Key Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China; Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan Tsuihang New District, Guangdong Province, 528400, PR China.
  • 6 State Key Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 7 State Key Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, PR China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China; Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan Tsuihang New District, Guangdong Province, 528400, PR China.
  • 8 School of Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Rd, Nanjing, 210023, PR China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing, 210023, PR China. Electronic address: xxyu@njucm.edu.cn.
  • 9 State Key Laboratory of Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, PR China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China. Electronic address: jli@simm.ac.cn.
  • 10 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, PR China; Innovation Center for AI and Drug Discovery, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China. Electronic address: slzhu@chem.ecnu.edu.cn.
PMID: 40112662 DOI: 10.1016/j.ejmech.2025.117512
Abstract

Targeted protein degradation (TPD) technology is a promising strategy for drug development, while the on-target off-tumor risks of current TPD technologies were intractable. Herein, a series of (HSP90)-mediated targeting chimeras (HEMTACs) based WEE1-target degraders were designed to enhance the efficiency and decrease off-tumor risks. Among them, 8b and 9c could effectively degrade cellular Wee1 protein and exhibited superior anti-proliferative activity in MV-4-11 cells by inducing cell cycle arrest in G2/M phase. Meanwhile, 8b and 9c exhibited high selectivity to primary AML cells over normal cells. Furthermore, 3 mg/kg of 9c demonstrated superior anti-cancer activity than 5 mg/kg AZD1775 in an AML PDX model. And most importantly, 9c exhibited lower hematotoxicity than equimolar AZD1775 in mice safety evaluation, suggesting that 9c is a promising degrader for AML target therapy, comfirming that HSP90-based HEMTACs is a valid strategy to reduce off-tumor risks.

Keywords

Anti-AML; HSP90; Hematotoxicity; Targeted protein degradation; WEE1.

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