Abstract 6378: Brain-penetrant molecular glue degraders targeting ALK via a novel degron: a potential therapeutic approach for ALK-positive NSCLC

Abstract Aberrant expression of anaplastic lymphoma kinase (ALK) is the oncogenic driver of 3-7% of non-small cell lung cancer (NSCLC) cases. Six ATP-competitive tyrosine kinase inhibitors (TKIs) of ALK have been approved by the FDA to treat patients with ALK-positive NSCLC, but mutations conferring drug resistance often occur in the ATP-binding pocket of ALK signifying a need for alternative modalities to inhibit ALK function. Here we report that ALK-driven tumor growth can be suppressed by novel molecular glue cereblon E3 ligase modulatory drugs (CELMoDs) that trigger ubiquitylation and subsequent proteasomal degradation of ALK. A cryo-EM structure of the ALK-CELMoD-cereblon ternary complex revealed that ALK interacts with cereblon and drug through a site distal to its ATP-binding pocket and features a surprising degron structure distinct from the canonical G-loop degron established for other cereblon neosubstrates. Subsequent lead optimization identified a series of ALK CELMoDs with improved brain penetration. Our in vitro and in vivo studies support the hypothesis that a brain penetrant ALK CELMoD would be an effective therapy for ALK-positive NSCLC with similar or better efficacy and safety profile compared to TKIs. Furthermore, combination treatment with TKIs might enhance ALK CELMoD efficacy due to distinct binding sites and mechanisms of action. Finally, the novel degron suggests that the degradome of CELMoDs goes beyond G-loop-containing proteins, thus emphasizing the importance and potential of this modality to target a wide spectrum of previously un-druggable proteins in human diseases. Citation Format: Zheng Wang, Massimo Ammirante, Martina Malatesta, Alex Cortez, Young Chen, Jinyi Zhu, Dahlia Weiss, Vijaya Lakshmi Dommeti, Geraldine Hernandez, Joshua M. Baughman, Adwait Sathe, Matthew Groza, Maria Donoso, Roxxana Beltran, Regina Paramitha, Ryan Davison, Atefeh Garzan, Barbra Pagarigan, Michelle Slade, Jacobo Fuentes, Jennifer Buenviaje, Shan Yu, Xinde Zheng, Andres H de la Peña, Mariko Riley, Gabe Mintier, Surendra Nayak, Shuichan Xu, Rama Narla, Ellen Filvaroff, Deborah Mortensen, Lihong Shi, Celia Fontanillo Fontanillo, Christoph Zapf, Neil Bence, Mark Rolfe. Brain-penetrant molecular glue degraders targeting ALK via a novel degron: a potential therapeutic approach for ALK-positive NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6378.