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 J26 and bornane-based
HyT J21 demonstrated significant degradation and antiproliferative
activity in vitro. J26 achieves effective degradation
of the EML4-ALK fusion protein in H3122 cells with CRBN expression
knocked down via siRNA. In vivo, J26 significantly suppresses
tumor growth with moderate oral bioavailability. Remarkably, J26 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.