2. Academic Validation
  3. Development of Adamantane-based hydrophobic tags targeting anaplastic lymphoma kinase with enhanced antitumor activities

Development of Adamantane-based hydrophobic tags targeting anaplastic lymphoma kinase with enhanced antitumor activities

  • Bioorg Chem. 2025 Sep:164:108876. doi: 10.1016/j.bioorg.2025.108876.
Jingjie Zhu 1,  Fangyi Zhan 1,  Jia Xie 1,  Tonghao Fang 1,  Yuan Sun 1,  Feiyan Zhan 1,  Tian Gao 1,  Jingyu Liu 1,  Jiajie Feng 1,  Pijun Zhou 1,  Huajian Zhu 1,  Hong Yao 1,  Zheying Zhu 2,  Shengtao Xu 3,  Jinyi Xu 4,  Shaowen Xie 5
Affiliations

Affiliations

  • 1 School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
  • 2 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
  • 3 School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: cpuxst@cpu.edu.cn.
  • 4 School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: jinyixu@china.com.
  • 5 School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: xieshaowen618@163.com.
PMID: 40865230 DOI: 10.1016/j.bioorg.2025.108876
Abstract

Anaplastic lymphoma kinase (ALK) has emerged as a critical molecular target for therapeutic intervention in various malignancies, with a particular focus on non-small cell lung Cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). In this work, we utilized the hydrophobic tagging (HyT) strategy to design and synthesize a series of novel ALK-targeting degraders, which were constructed by linking the derivative A3 based on ALK inhibitor alectinib to a HyT fragment adamantane via various customized linkers. The most promising compound, H7, demonstrated potent ALK degradation activity both in vitro and in vivo, along with potent anti-proliferative effects in ALK-dependent cell lines, while showing minimal cytotoxicity in cells lacking ALK fusion proteins. Furthermore, it was found that the degradation process mediated by compound H7 occurred via the ubiquitin-proteasome system, with chaperones playing a vital role in the process. These findings offer promising insights for the development of effective degraders targeting ALK, potentially advancing therapeutic strategies in ALK-related diseases.

Keywords

Adamantane; Anaplastic lymphoma kinase; Degraders; Hydrophobic tags; Protein degradation.

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