PRLX 93936 / Prolexys - LARVOL DELTA

Therapeutic targeting of the nuclear pore complex with molecular glue degraders in pancreatic cancer Free (AACRPanCa 2025) - "PRLX-93936, a derivative of erastin, was previously tested in early-phase oncology clinical trials despite having an unknown mechanism. 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."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • KRAS • TRIM21

Defining the antitumor mechanism of action of a clinical-stage compound as a selective degrader of the nuclear pore complex. (PubMed, Cancer Discov) - "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 nuclear pore complex...Direct compound binding to TRIM21 was confirmed via surface plasmon resonance and x-ray crystallography, while compound-induced TRIM21-nucleoporin 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 with robust pharmacokinetics and efficacy against pancreatic cancer xenografts and patient-derived organoids."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • TRIM21

Elaboration of molecular glues that target TRIM21 into TRIMTACs that degrade protein aggregates. (PubMed, Nat Commun) - "Additionally, we elaborate PRLX-93936 to a heterobifunctional degrader that uses wild-type TRIM21 to degrade a multimeric protein. Together, our work creates opportunities for targeted protein degradation and enables the design of additional TRIM21-targeting glues and Proteolysis-Targeting Chimeras (PROTACs)."

Journal • Oncology • Targeted Protein Degradation • TRIM21

TRIM21-NUP98 Interface Accommodates Structurally Diverse Molecular Glue Degraders. (PubMed, ACS Chem Biol) - "Here, we analyzed public compound toxicity data across a large collection of cell lines and identified two additional molecular glue degraders, PRLX 93936 and BMS-214662, which engage the TRIM21-NUP98 interface to induce selective degradation of nuclear pore proteins. Additionally, we confirmed that HGC652, another TRIM21-dependent molecular glue degrader, also binds at this interface. Together with our previously characterized degrader (S)-ACE-OH, these findings demonstrate that the TRIM21-NUP98 interface can accommodate structurally diverse molecular glue degraders."

Journal • Targeted Protein Degradation • NUP98 • TRIM21

Cisplatin synergizes with PRLX93936 to induce ferroptosis in non-small cell lung cancer cells. (PubMed, Biochem Biophys Res Commun) - "In the current study, we showed that cisplatin and PRLX93936, an analog of erastin that has been tested in clinical trials, demonstrated synergistic effects against non-small cell lung cancer (NSCLC) cells. Nrf2 silencing increased this sensitivity while inhibition of Keap1 attenuated it. Overall, our data reveal a new effective treatment for NSCLC by synergizing cisplatin and PRLX93936 to induce ferroptosis."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • GPX4