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Tsinghua University's Latest Cell

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Targeted protein degradation (TPD) utilizes molecular glue or targeted proteolytic chimeras (PROTACs) to eliminate pathogenic proteins by facilitating their interaction with E3 ubiquitin ligase. Current TPD methods are limited to relying on E3 ubiquitin ligases with a small number of constitutive activities.

On November 1, 2024, Tsinghua University Han Ting and scalpers jointly communicated inCellmagazinePublished online entitled“Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders”The research paper,The studyIt is reported that the metabolite (S)-ACE-OH of the antipsychotic drug acepromazine as a molecular glue induces an interaction between the E3 ubiquitin ligase TRIM21 and the nucleoporin NUP98, resulting in nucleoporin degradation and disruption of nucleocytoplasmic trafficking.

Acepromazine functionalization PROTACs the ability to selectively degrade multimeric proteins, such as multimeric proteins in biomolecular aggregates, while retaining monomeric proteins. This selectivity is consistent with the requirement of substrate-induced clustering for TRIM21 activation. diseases such as autoimmunity, neurodegeneration, and cancer due to abnormal protein assembly,The findings highlight the potential of TRIM21-based multi-selective degradants as a strategy to address the immediate causes of these diseases.

Targeted protein degradation (TPD) by chemically inducing proximity between the E3 ubiquitin ligase and the target protein is an emerging therapeutic modality for addressing proteins considered untreatable by traditional small molecule inhibitors. Two major chemical degraders have been used for TPD: monovalent molecular gels (MGs) and bifunctional proteolytic targeting chimeras (PROTACs). MGs are drug-like compounds that utilize complementary protein interfaces to induce cooperative interactions between E3 ubiquitin ligases and targets. Immunomodulatory iminoids (IMiDs) such as lenalidomide and pomalidomide highlight the influence of MGs, which as MGs induce the degradation of a series of new substrates, resulting in specific therapeutic effects in patients with multiple myeloma. The subsequent discovery of anticancer arylsulfonamides and CDK12 inhibitors as MGs has revealed their broader prevalence than initially recognized. Despite the growing variety of MGs, their discovery remains largely accidental.

In contrast, PROTACs is a bifunctional molecule that includes a target protein binder, an E3 ubiquitin ligase binder, and a linker.Although challenges such as selectivity and pharmacokinetics remain, ongoing research efforts are dedicated to improving the design of PROTAC and unlocking its full therapeutic potential in various diseases, especially tumors.Recently, a large number of rationally designed PROTACs targeting disease-causing proteins have entered clinical trials, providing proof of concept for the efficacy and safety of PROTACs in human patients.

One area where selective TPD would be an attractive technology is the therapeutic targeting of biomolecular aggregates, which are membrane-free assemblies enriched for specific proteins and nucleic acids in a subcellular environment. A number of recent studies have revealed the critical functions of biomolecular aggregates in normal and diseased states. In particular, abnormal protein aggregates are causally related to neurodegeneration, autoimmunity and cancer, thus revealing exciting therapeutic opportunities.The normal counterparts of these aberrantly associated proteins typically perform an indispensable function. However, the selective degradation of proteins in biomolecular aggregates without affecting the dilute phase has proven to be a technical challenge.

In this study, the authors propose TRIM21-mediated TPD as a general strategy to induce selective degradation of multimeric proteins. By combining phenotype-based screening and subsequent target deconvolution, it was determined that (S)-ACEOH is a MG between the E3 ubiquitin ligase TRIM21 and the nucleoporin protein NUP98, resulting in the degradation of several proteins within the multimeric nuclear pore complex (NPC).By analyzing the co-crystal structure of the PRYSPRY domain in the complex of TRIM21 and acepromazine and its metabolites, a ligand pocket suitable for PROTAC functionalization was found in TRIM21. Using this structural insight, a TRIM21-based PROTACs was designed, which PROTACs showed significant selectivity in degrading multimeric targets (such as targets in biomolecular aggregates) while retaining non-multimeric targets in dilute phase. These findings highlight the potential of TRIM21-based degradants to eliminate target proteins that cause disease through aberrant multimerization.

Researcher Han Ting and researcher Huang Niu of Beijing Institute of Life Sciences/Institute of Biomedical Intersection of Tsinghua University are the co-corresponding authors of this article. Lu Panrui, Cheng Yalong, Xue Lei and Ren Xintong of Huang Niu Laboratory are the co-first authors of this article. High-throughput screening was strongly supported by the Chemistry Center/Qi Xiangbing Laboratory, and Chen Chenglong of Li Chao Laboratory also made important contributions to the research.

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