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

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 gain of viability following pharmacological inhibition of the Ubiquitin-life modifier activating enzyme (UBA1/UAE). This approach revealed 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 have elaborated PRLX-93936 to the first ‘TRIMTAC’ that uses wild-type TRIM21 to degrade a multimeric protein. Together our work creates new opportunities for targeted protein degradation and enables the design of additional TRIM21-targeting glues and TRIMTACs.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Belinda Willard  

LAB HEAD: Drew Adams, PhD

PROVIDER: PXD062839 | Pride | 2025-06-17

REPOSITORIES: Pride