TRI-611

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.

In cell-free biochemical/biophysical assays, TRI-611 equally effectively promotes the interaction between CRBN and wild-type ALK as well as the ALKL1196M/G1202R composite mutant protein, as well as subsequent polyubiquitination[1].
TRI-611 effectively targets all 30 tested EML4-ALK mutant proteins in engineered Ba/F3 cells, including TKI-resistant variants [1].
TRI-611 potently inhibits the proliferation of ALK-positive non-small cell lung cancer (NSCLC) cell lines harboring various ALK TKI resistance alleles [1].
TRI-611 induces rapid, potent, and sustained CRBN-dependent degradation of the EML4-ALK fusion protein and oncogenic transmembrane ALK in ALK-positive cells, achieving a maximum degradation rate of >90% within 1–2 hours of treatment, with a recovery half-life exceeding 15 hours after drug withdrawal [2].
TRI-611 promotes the ubiquitination and degradation of ALK fusion alleles (including TKI-resistant mutants) and exerts a broader range of phenotypic effects on ALK fusion-driven NSCLC cell lines compared to ALK TKIs [3].

In mouse efficacy studies, TRI-611 caused regression of subcutaneous xenografts in CRISPR-edited EML4-ALK-mutant NCI-H3122 cells that were unresponsive to ALK TKIs [1].
TRI-611 exhibits oral bioavailability and blood-brain barrier permeability; daily oral administration achieves deep and sustained degradation of endogenous EML4-ALK, as well as tumor regression, in subcutaneous and intracranial xenograft models of ALK-positive NSCLC [2][3].