PRLX 93936 / Prolexys - LARVOL DELTA

The molecular basis for nuclear pore destruction by a proximity-inducing molecular glue. (PubMed, Cell Chem Biol) - "We and others recently discovered that the small molecule PRLX-93936 (PRLX), which was originally developed as an erastin derivative with antitumor activity, is a molecular glue that alters the substrate specificity of the TRIM21 ubiquitin ligase...We also report the discovery of an enhanced molecular glue, MAN-021, and describe its structure. Our findings provide a basis for rational development of next-generation small molecules with enhanced or differentiated activities."

Journal • Oncology • Targeted Protein Degradation • NUP98 • TRIM21

Discovery of TRIM21 molecular glues that drive potent anti-tumor efficacy via nuclear pore complex degradation (AACR 2026) - "Through a combination of large-scale phenotypic profiling, genome-scale functional genomics, and mass spectrometry-based proteomics, we discovered that the clinical drug PRLX-93936 (PRLX) is a molecular glue that binds and reprograms the TRIM21 E3 ubiquitin ligase to degrade the NPC, resulting in potent inhibition of pancreatic ductal adenocarcinoma (PDAC) cells...Ongoing work is focused on developing compounds with enhanced potency, evaluating drug combinations, and performing preclinical toxicology studies. The discovery of TRIM21-mediated NPC degraders presents an unexpected and promising new strategy for the treatment of PDAC and other challenging solid tumors."

Clinical • Head and Neck Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • NUP98 • TRIM21

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