Andrew R Conery, Daniel S La, Artyom A Alekseyenko, David Marcoux, Aaron G Bart, Matt L Harlow, Patrick R Arsenault, Nico R Cantone, Rebecca L Casaubon, Alexander Constan, Hari B Kamadurai, Aravind Prasad Medikonda, Duncan E Nunes, Hannah Szeto, Tim J Wigle, Maolin Yu, Aleksandra Zagulyaeva, Christine M Zarate, Lauren Highfield, Nobuyuki Kondo, Aaron N Hata, Kenneth Ngo, Jisu Lee, Prafulla C Gokhale, Caroline Germa, Kathleen I Seyb, Patrick Trojer, Vito J Palombella
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 .