Work

Elaboration of molecular glues that target TRIM21 into TRIMTACs that degrade protein aggregates

Year: 2025

Type: article

Abstract: Although molecular glues have emerged as innovative tools within the field of chemically induced proximity, approaches for their discovery remain limited. Here we report a phenotypic screening approach in which small molecules whose cytotoxic mechanisms require ubiquitination show gain of viability following pharmacological inhibition of the E1 enzyme UAE. This approach revealed two previously clinically-evaluated cytotoxins of unknown mechanism, PRLX-93936 and BMS-214662, as molecular glues that directly target the E3 ubiquitin ligase TRIM21. These molecules induce TRIM21-mediated proteasomal degradation of multiple nucleoporin proteins, leading to inhibition of nuclear export and ultimately cell death. Loss of nucleoporins and nuclear export accounts for past observations in which BMS-214662 led to disrupted subcellular protein localization. Furthermore, the cytotoxicity of these agents correlates strongly with TRIM21 expression, suggesting clinical re-evaluation of these agents in patients with TRIM21-high cancers. Additionally, relative to recently-reported TRIM21-targeting glues, these two scaffolds display high cellular potency, creating new opportunities for targeted protein degradation via the design of additional glues and "TRIMTACs".

Source: Nature Communications

DOI: 10.1038/s41467-025-61818-7