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TRI-611, a selective, brain-penetrant molecular glue degrader of ALK

Published: 09/09/2026, 12:00 AM

Nature (2026) Cite this article Tyrosine kinase inhibitors (TKIs) targeting anaplastic lymphoma kinase (ALK) have transformed the treatment landscape of ALK fusion-positive non-small-cell lung carcinoma (ALK-positive NSCLC), but the limited options for patients who progress on approved TKIs highlight a continued need for an orthogonal therapeutic approach1,2. TRI-611 is a potent, brain-penetrant molecular glue degrader of ALK fusion proteins with the potential to address this need. TRI-611 promotes the proximity of the ALK kinase domain and CRL4 substrate adaptor CRBN through a unique degron interface distal from the kinase active site. The unique binding interface of TRI-611 leads to selectivity across the proteome including known CRBN neosubstrates and other kinases. TRI-611 treatment induces degradation of all forms of ALK fusion proteins, including wild-type and ALK TKI-resistant versions, leading to regression of cell line and patient-derived subcutaneous and intracranial tumour models of ALK-positive NSCLC. TRI-611 can be combined with orthosteric ALK TKIs, achieving synergistic and durable tumour regressions. TRI-611 represents to our knowledge the first clinical-stage molecular glue degrader targeting an oncogenic gene fusion and has the potential to expand the arsenal of therapeutic options for patients with ALK-positive NSCLC . This is a preview of subscription content, access via your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription Prices may be subject to local taxes which are calculated during checkout Proteomics data have been deposited at MassIVE under accession number MSV000099079. RNA-seq data have been deposited at the NCBI GEO repository under accession number GSE329452. Structural data have been deposited at the EMDB (EMD-752353, EMD-72684 and EMD-72685) and PDB (9XZG). Source data are provided with this paper. Schneider, J. L., Lin, J. J. & Shaw, A. T. ALK-positive lung cancer: a moving target. Nat Cancer 4, 330–343 (2023). Article CAS PubMed PubMed Central Google Scholar Voena, C., Ambrogio, C., Iannelli, F. & Chiarle, R. ALK in cancer: from function to therapeutic targeting. Nat. Rev. Cancer 25, 359–378 (2025).