Abstract ND07: TRI-611, a potent, selective, CNS-penetrant ALK molecular glue degrader for the treatment of ALK-fusion protein positive non-small cell lung cancer

Abstract While lung cancer remains the leading cause of cancer deaths worldwide, our understanding of genetic drivers of certain lung cancer subtypes has enabled significant progress in precision medicine approaches. Therapeutic inhibition of Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase has transformed the treatment of ALK fusion-positive non-small cell lung carcinoma (NSCLC), but ALK-targeted tyrosine kinase inhibitors (TKIs) can be limited by toxicities from off-target activity, insufficient brain penetration, and acquired resistance including mutations that impact TKI binding. Molecular glue degraders that eliminate disease drivers by engaging the ubiquitin/proteasome system via the CRL4CRBN E3 ligase are an alternative therapeutic approach. Here we describe TRI-611, a potent, brain-penetrant, cereblon-utilizing molecular glue degrader that enables recognition of ALK via a novel degron that is distal from the orthosteric TKI binding site. TRI-611 promotes the ubiquitination and degradation of ALK fusion proteins, including those with clinically relevant acquired TKI resistance mutations. A high-resolution cryo-EM structural model of the ALK:TRI-611:CRBN complex reveals a unique, non-G-loop surface degron interface that results in exquisite selectivity over other CRBN neosubstrates and across the global proteome. Importantly, this selectivity also encompasses closely related kinases such as the Neurotrophic Tyrosine Kinase Receptor (NTRK) family, whose inhibition is associated with dose-limiting neurotoxicity of ALK TKIs. TRI-611 promotes tumor regression in preclinical subcutaneous and intracranial cell line and subcutaneous patient-derived xenograft models of ALK+ NSCLC with once daily oral dosing, demonstrating the ability of TRI-611 to target both extracranial and intracranial tumors. Further, the distinct binding sites of TRI-611 and orthosteric TKIs enable combination treatment, which leads to synergistic antitumor efficacy and more durable tumor regressions relative to TKI monotherapy in tumor xenografts. TRI-611 may have the potential to transform the treatment of ALK+ NSCLC and, having completed IND-enabling studies, represents the first clinical stage molecular glue degrader of an oncogenic fusion protein. Citation Format: Vito J. Palombella, Daniel S. La, Andrew R. Conery, Artyom A. Alekseyenko, David Marcoux, Aaron G. Bart, Matt L. Harlow, Patrick R. Arsenault, Nico R. Cantone, Rebecca L. Casaubon, Hari B. Kamadurai, Aravind Prasad Medikonda, Duncan E. Nunes, Tim J. Wigle, Maolin Yu, Aleksandra Zagulyaeva, Christine Zarate, Kenneth Ngo, Jisu Lee, Prafulla C. Gokhale, Kathleen I. Seyb, Patrick Trojer. TRI-611, a potent, selective, CNS-penetrant ALK molecular glue degrader for the treatment of ALK-fusion protein positive non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr ND07.