Dear Editor,

Targeted protein degradation (TPD) represents a promising research field that has quickly attracted attention and efforts from both academia and pharmaceutical industry. TPD technology uses small molecules to induce the degradation of target proteins by harnessing the ubiquitin–proteasome system. PROTAC (PROteolysis Targeting Chimeras)1,2,3 and MG (Molecular Glue)4,5 are two major modes of TPD. PROTACs comprise three parts, including a ligand for binding a target protein, another ligand for recruiting an E3 ligase, and a linker, which helps anchoring the target protein to the E3 ubiquitin ligase, to promote its ubiquitination and subsequent proteasomal degradation. Similar to PROTACs, MGs can also cause ubiquitination and degradation of a target protein. In contrast to PROTACs, MG molecules are small-molecular-weight compounds that trigger a compact protein–protein interaction between a target protein and an E3 ubiquitin ligase. Both PROTACs and MGs have their own advantages and limitations. For example, PROTACs are more suitable for rational design, and a broad range of targets have been successfully degraded using the PROTAC approach. However, PROTACs are often relatively large and sometimes suffer from insufficient druggability. In contrast, MG molecules have a clear advantage in their smaller molecular weights and better druggability. However, the design of MGs is rather difficult due to limited understanding of the controlling factors, and there have been few successful cases.6,7 Therefore, we planned to design molecules with the characteristics of these two techniques to combine their strengths in this study.

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