Overcoming E3 Ligase-Mediated Resistance: Development of Novel Hydrophobic Tagging-Based Degraders Targeting ALK Protein

Traditional PROTACs, despite their groundbreaking role in targeted protein degradation (TPD), rely on E3 ubiquitin ligases and are vulnerable to resistance. In this study, we discovered norbornene- and bornane-based hydrophobic tags (HyTs) that efficiently degrade anaplastic lymphoma kinase (ALK). Notably, a novel hydrophobic tag, bornane was first identified. Both norbornene-based HyT <b>J26</b> and bornane-based HyT <b>J21</b> demonstrated significant degradation and antiproliferative activity in vitro. <b>J26</b> achieves effective degradation of the EML4-ALK fusion protein in H3122 cells with CRBN expression knocked down via siRNA. In vivo, <b>J26</b> significantly suppresses tumor growth with moderate oral bioavailability. Remarkably, <b>J26</b> effectively targets ALK through the Hsp70 chaperone system and the ubiquitin-proteasome pathway, by passing the need for E3 ligase CRBN. This feature addresses a potential resistance mechanism arising from E3 ligase downregulation, thereby enhancing the potential of HyT technology in precision oncology.