ArticleNature communications2025
Elaboration of molecular glues that target TRIM21 into TRIMTACs that degrade protein aggregates.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Ubiquitin E3 ligase activity in TRIpartite Motif (TRIM) family proteins.Biochemical Society transactions · 2026Review
- Nucleoporins in Cancer: Functional Roles and Therapeutic Opportunities.Cancer discovery · 2026Article
- High-throughput ligand diversification to discover chemical inducers of proximity.Nature chemical biology · 2026Article
- Unraveling the Multifaceted Role of TRIM21 in Virus-Triggered Innate Immunity and Diseases.Biomolecules · 2026Review
- Redirecting TRIM21 with TRIMTACs for the targeted degradation of multimeric proteins.The FEBS journal · 2026Review
- The molecular basis for nuclear pore destruction by a proximity-inducing molecular glue.Cell chemical biology · 2026Article
- TRIM21 induces selective autophagy of viruses and bacteria.Molecular cell · 2026Article
- A Degron Decoy System Co-opts Pathological Seeding to Enable Clearance of Multimeric α-Synuclein.bioRxiv : the preprint server for biology · 2026Article
- Clues for glues: from serendipity to nature's blueprints in degrader discovery.Essays in biochemistry · 2025Review
- Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex.Cancer discovery · 2025Article
- State-selective small molecule degraders that preferentially remove aggregates and oligomers.Nature communications · 2025Article
Corrections and comments
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Approaches for the discovery of molecular glues remain limited. Here we report a phenotypic screening approach in which cytotoxins whose mechanisms require ubiquitination show a gain of viability following pharmacological inhibition of the Ubiquitin-like modifier activating enzyme (UBA1/UAE). This approach reveals PRLX-93936 and BMS-214662 as molecular glues that directly target the E3 ligase TRIM21 to induce degradation of nucleoporin proteins and inhibit nuclear trafficking. The cytotoxicity of these agents correlates strongly with TRIM21 expression, suggesting re-evaluation of these clinically tested agents in patients with TRIM21-high cancers. Relative to recently disclosed TRIM21-targeting glues, PRLX-93936 and newly-synthesized analogs represent a distinct structural series, lack known cellular off-targets, and offer greatly enhanced potency. 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).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.