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

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.