Targeting E3 ligases of the TRIM family for the development of next generation degraders

Targete protein degradation, driven by the clinical success of PROTACs (proteolysis targeting chimeras) and molecular glues, has significantlycontributed to the drug development pipeline. However, current degrader design predominantly relies on a limited set of E3 ubiquitin ligases, such as Cereblon and Von Hippel-Lindau. Exploring the chemical toolbox to include new, untargeted E3 ligases is important for developing degraders with new properties such as tissue-specific degradation. The present review highlights recent advancements in targeting the tripartite motif (TRIM) family of E3 ligases. Over the past 3 years, the discovery of TRIM ligands established the druggability of several members of this family, enabling the development of new degraders. However, so far reported ligands cover only two of the twelve known subclasses of this family. The present review focuses on ligands that target the substrate recruitment domain of TRIMs targeting the PRY-SPRY domains of TRIM7, TRIM21, TRIM25, and TRIM58, as well as the PHD-bromodomain of TRIM24 and TRIM33. Notably, some of these ligands have enabled the development of efficient PROTACs and molecular glues. For example, ligands for TRIM21 have been used for PROTAC development (TrimTACs) to degrade multimeric protein, and highly potent glues have been developed to degrade components of the nuclear pore complex. TRIM24 is not an active E3 ligase, but bromodomain ligands have been exploited for the development of TRIM24 degraders with potential applications in oncology. Thus, recent developments in TRIM-targeting ligands have significantly extended the toolbox for degrader development.