PRLX 93936

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.

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).

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.