Molecular glue degraders that recruit E3 ubiquitin ligases have transformed the treatment of certain hematologic malignancies, yet their broader application to solid tumors has been limited by the historically serendipitous nature of discovery and a lack of tractable ligase targets. This Drug Discovery Award addresses this gap by advancing a newly identified class of molecular glues that engage the E3 ligase TRIM21, a protein expressed in multiple solid tumors, including pancreatic ductal adenocarcinoma. Pancreatic cancer remains one of the deadliest malignancies, with few effective targeted therapies and a median survival of less than one year for advanced disease. A central challenge in the field is how to rationally deploy molecular glue strategies to selectively kill solid tumor cells while sparing normal tissues.
Building on extensive mechanistic and chemical biology studies, the team has established that these molecules bind TRIM21 and induce a novel degradation pathway involving nuclear pore components, leading to loss of short-lived pro-survival transcripts and selective cancer cell death. The project will optimize lead compounds using structure-guided medicinal chemistry, informed by high-resolution structural data and quantitative assays of ternary complex formation. The team will evaluate optimized molecules in isogenic cell systems, patient-derived pancreatic cancer organoids, and in vivo tumor models to define pharmacokinetic–pharmacodynamic relationships, therapeutic efficacy, and biomarker strategies. Parallel safety, metabolism, and immune modulation studies will guide the selection of a development candidate suitable for future clinical development.
This work will extend the molecular glue paradigm through a defined, mechanistically grounded approach. By directly targeting TRIM21-dependent vulnerabilities, the project aims to deliver a first-in-class therapeutic strategy with the potential for meaningful single-agent activity in pancreatic and other TRIM21-expressing cancers, ultimately opening a new avenue for patients with few existing treatment options.