TRI-611 is a highly selective ALK molecular chaperone degrader that can cross the blood-brain barrier. By binding to the CRBN E3 ligase, it induces the ubiquitination and proteasomal degradation of ALK fusion proteins. TRI-611 efficiently degrades various EML4-ALK fusion proteins, including TKI-resistant mutants, and demonstrates significant antitumor activity in ALK-positive non-small cell lung cancer (NSCLC) models. TRI-611 induces tumor regression in subcutaneous and intracranial xenograft models and is equally effective in models resistant to ALK tyrosine kinase inhibitors (TKIs), making it a valuable tool for research into ALK-driven tumors and resistance mechanisms.