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Through large-scale phenotypic profiling of cancer cell lines, genome-scale functional genomic modifier screens, and mass spectrometry\u2013based 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. Upon compound-induced TRIM21 recruitment, the nuclear pore is ubiquitylated and degraded, resulting in the loss of short-lived cytoplasmic mRNA transcripts and the induction of cancer cell apoptosis. Direct compound binding to TRIM21 was confirmed via surface plasmon resonance and X-ray crystallography, whereas compound-induced TRIM21\u2013nucleoporin complex formation was demonstrated through multiple orthogonal approaches in cells and in vitro. Phenotype-guided optimization yielded compounds with 10-fold greater potency and drug-like properties, along with robust pharmacokinetics and efficacy against pancreatic cancer xenografts and patient-derived organoids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>This study establishes the cancer therapeutic potential of optimized TRIM21 molecular glues to degrade the NPC and underscores the value of reexamining drugs with previously unknown mechanisms using current technologies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0271","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T11:37:00Z","timestamp":1756813020000},"page":"2505-2529","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Defining the Antitumor Mechanism of Action of a 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