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

Tyrosine kinase inhibitors (TKIs) targeting Anaplastic Lymphoma Kinase (ALK) have transformed the treatment landscape of ALK fusion-positive non-small cell lung carcinoma (NSCLC), but limited options for patients who progress on approved TKIs highlight a continued need for an orthogonal therapeutic approach. TRI-611 is a potent, brain-penetrant molecular glue degrader (MGD) of ALK fusion proteins with the potential to address this need . TRI-611 promotes the proximity of the ALK kinase domain and CRBN via 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 neo-substrates and other kinases. TRI-611 treatment induces degradation of all forms of oncogenic ALK fusion proteins, including TKI-resistant mutated versions of ALK, 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 the first example of a clinical stage MGD targeting an oncogenic gene fusion and has the potential to expand the arsenal of therapeutic options for ALK-positive NSCLC patients.