Abstract B003: Therapeutic targeting of the nuclear pore complex with molecular glue degraders in pancreatic cancer

Abstract Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting an unrealized opportunity for selective therapeutic inhibition of the nuclear pore complex (NPC). Through large-scale phenotypic profiling of cancer cell lines, genome-scale functional genomic modifier screens, and mass spectrometry-based proteomics, we discovered that the clinical drug PRLX-93936 is a molecular glue that binds and reprograms the TRIM21 ubiquitin ligase to degrade the NPC resulting in inhibition of pancreatic ductal adenocarcinoma (PDAC) cells. PRLX-93936, a derivative of erastin, was previously tested in early-phase oncology clinical trials despite having an unknown mechanism. Upon compound-induced TRIM21 recruitment, the NPC is ubiquitylated and degraded, resulting in the loss of short-lived pro-survival cytoplasmic mRNA transcripts and induction of cancer cell apoptosis. Direct compound binding to TRIM21 was confirmed via surface plasmon resonance and x-ray crystallography, and compound-induced TRIM21-nucleoporin complex formation was demonstrated through multiple orthogonal approaches in cells and in vitro. Using PRLX-93936 as a starting point, phenotype-guided optimization yielded novel compounds with 10-fold greater potency and improved drug-like properties with robust pharmacokinetics. Following compound optimization, robust TRIM21 biomarker performance was confirmed using the PRISM multiplex cell viability assay. Although the NPC is an essential cellular structure, prior studies suggest that a therapeutic index for temporary NPC inhibition exists in cancer cells versus normal tissues. To evaluate this potential therapeutic index, we compared PDAC cancer cell viability over time versus non-malignant hTERT-RPE1 cells using live-cell imaging. Treatment with compounds at moderate concentrations for defined durations slowed hTERT-RPE1 proliferation, whereas PDAC cells underwent rapid and irreversible cell death. These findings support a model where temporary, TRIM21-mediated NPC degradation preferentially induces cancer cell death. To establish translational potential for this mechanism, we employed a combination of three-dimensional patient-derived PDAC organoid models and in vivo cell line xenografts. We prospectively selected human tumor organoids from the HCMI project with high or low TRIM21 expression by RNA-seq. As predicted, TRIM21 expression was predictive of compound efficacy. Robust anti-PDAC efficacy was also confirmed in vivo using multiple KRAS-mutant cell lines. Our work demonstrates the power of unbiased phenotypic screening coupled with orthogonal approaches toward target identification, functional validation, and deciphering of mechanism of action. Planned next steps include evaluating drug combinations and further pre-clinical toxicology for de-risking. The discovery of potent TRIM21-mediated NPC degraders presents unexpected new opportunities for PDAC therapy. Citation Format: Linjie Yuan, Wenzhi Ji, Brendan G. Dwyer, Joey Lu, Jing Bian, Gianna M. Colombo, Michael J. Martinez, Daniel Fernandez, Nick A. Phillips, Michelle T. Tang, Christine W. Zhou, Hannah M. Jones, Nirk Quispe. Calla, Cesar Guzman. Huancas, Michael Eckart, Jessica Tran, Tian Qiu, John G. Doench, Matthew G. Rees, Jennifer A. Roth, Michael D. Cameron, Gregory W. Charville, Calvin J. Kuo, Scott J. Dixon, Tinghu Zhang, Stephen M. Hinshaw, Nathanael S. Gray, Steven M. Corsello. Therapeutic targeting of the nuclear pore complex with molecular glue degraders in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B003.