Abstract 6737: Selective degradation of pathologic multimers via a novel TRIM21-engaging molecular glue and PROTAC platform.

Abstract Background: Targeted protein degradation (TPD) holds great promise for cancer therapy, but its application is often constrained by the limited repertoire of E3 ligases and the challenge of selectively eliminating pathologic protein assemblies, such as those driving oncogenesis, while sparing monomeric forms. The E3 ligase TRIM21 is a compelling yet underexplored effector, as its activation is hypothesized to require substrate multimerization, potentially conferring intrinsic selectivity for diseased-associated protein complexes. Methods and Results: We report a novel TPD strategy centered on the activation of TRIM21. Initially, we discovered that (S)-ACE-OH, a metabolite of acepromazine, functions as a molecular glue by inducing a productive interaction between TRIM21 and the multimeric Nuclear Pore Complex (NPC) component NUP98. To systematically map the specificity and scope of this degradation event, we employed quantitative and TurboID proteomics. This analysis confirmed the potent and selective degradation of multiple NPC proteins, consistent with the disruption of a large multiprotein complex. Crucially, monomeric proteins remained unaffected, validating the hypothesized multimer-selectivity of TRIM21-based degradation. This selectivity was further demonstrated by engineering acepromazine-based PROTACs, which effectively degraded diverse multimeric client proteins, including components of biomolecular condensates. Conclusion: Our work establishes TRIM21 as a promising new E3 ligase for TPD, capable of selectively targeting multimeric proteins and pathologic assemblies. The proteomic analyses were pivotal in unequivocally defining this unique selectivity profile,​ providing a robust experimental foundation for this platform. This TRIM21-based degradation strategy opens a new therapeutic avenue for directly targeting undruggable, multimeric oncoproteins, with broad implications for cancer treatment. Citation Format: Niu Huang, Aijuan Yu, Yi Liu, Naizhong Zheng, Ting Han. Selective degradation of pathologic multimers via a novel TRIM21-engaging molecular glue and PROTAC platform abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6737.