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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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