Selective degradation of multimeric proteins via chemically induced proximity to TRIM21

Abstract

Targeted protein degradation (TPD) has emerged as an effective strategy to eliminate disease-causing proteins by inducing their interactions with the protein degradation machinery. First-generation TPD agents exploit a limited set of broadly expressed E3 ubiquitin ligases with constitutive activity, forbidding their application to proteins requiring higher levels of targeting selectivity. Here, by phenotype-based screening, we discovered that the antipsychotic drug acepromazine possesses interferon-enhanced cytotoxicity towards cancer cell lines expressing high levels of aldo-keto reductases 1C. These enzymes convert acepromazine into its stereo-selective metabolite (S)-hydroxyl-acepromazine, which recruits the interferon-induced E3 ubiquitin ligase TRIM21 to the vicinity of the nuclear pore complex, resulting in the degradation of nuclear pore proteins. Co-crystal structures of acepromazine and derivatives in complex with the PRYSPRY domain of TRIM21 revealed a ligandable pocket, which was exploited for designing heterobifunctional degraders. The resulting chemicals selectively degrade multimeric proteins-- such as those in biomolecular condensates--without affecting monomeric proteins, consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies have been causally linked to diseases such as neurodegeneration, autoimmunity, and cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.