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

Abstract

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 approach^1,2. 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 .