Abstract B064: TRI-611, a selective, CNS-penetrant molecular glue degrader of ALK with anti-tumor activity against preclinical models of ALK-fusion positive non-small cell lung cancer including kinase inhibitor refractory tumors

Abstract 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 tyrosine kinase inhibitors (TKIs) are limited by toxicity, central nervous system (CNS) metastasis, and acquired resistance. Molecular glue degraders that eliminate disease drivers by engaging the ubiquitin/proteasome system are a promising alternative approach that may not be subject to the same liabilities as enzymatic inhibitors. Here we describe TRI-611, a potent, brain-penetrant molecular glue degrader that enables E3 ligase recognition of ALK via a degron that is distal from the orthosteric site of TKI binding. Using biochemical, biophysical, and cellular studies, we show that TRI-611 promotes the ubiquitination and degradation of ALK fusion alleles, including those with clinically relevant acquired TKI resistance mutations, and as a result has a broader phenotypic impact on ALK fusion-driven cell lines than ALK TKIs. TRI-611 is CNS penetrant and promotes tumor regression with daily oral dosing in both subcutaneous and intracranial models of ALK+ NSCLC. The distinct binding interface of TRI-611 leads to broad selectivity across the global proteome including closely related kinases such as NTRK1, allowing for sustained high target coverage, including in the CNS, without the off-target liabilities that are associated with TKIs. TRI-611 is currently in IND-enabling studies with the potential to transform the treatment of ALK+ NSCLC and would represent the first clinical stage molecular glue degrader of an oncogenic fusion protein. Citation Format: 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, Vito J. Palombella, Kathleen I. Seyb, Tim J. Wigle, Maolin Yu, Aleksandra Zagulyaeva, Christine Zarate, Daniel S. La. TRI-611, a selective, CNS-penetrant molecular glue degrader of ALK with anti-tumor activity against preclinical models of ALK-fusion positive non-small cell lung cancer including kinase inhibitor refractory tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B064.