TRI-611 is an oral, blood-brain barrier-penetrating ALK molecular chaperone degrader. TRI-611 specifically binds to E3 ligases, recruits and marks oncogenic ALK fusion proteins, and mediates their selective degradation via the ubiquitin-proteasome system. TRI-611 induces tumor regression in xenograft models of ALK-positive NSCLC. TRI-611 is equally effective in TKI-resistant tumor models. TRI-611 is suitable for use in studies of ALK-positive non-small cell lung cancer and TKI-resistant tumors.

TRI-611 effectively targets all 30 EML4-ALK mutant proteins tested 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 and patient-derived ALK+ NSCLC cells harboring various ALK TKI resistance alleles. [1]
TRI-611 induces rapid, potent, and sustained CRBN-dependent degradation of the EML4-ALK fusion protein and the 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 phenotypic impact on ALK fusion-driven NSCLC cell lines compared to ALK TKIs. [3]
TRI-611 exhibits broad selectivity across the proteome (including kinases such as NTRK1), enabling sustained high target coverage—including in the central nervous system—without the off-target risks associated with TKIs.[3]

In a mouse xenograft model, TRI-611 induced regression of subcutaneous xenografts derived from CRISPR-engineered EML4-ALK-mutant NCI-H3122 cells that were refractory to ALK tyrosine kinase inhibitors (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]