Targeted degradation of c-Myc through the midnolin–proteasome pathway

Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy; however, most TPD technologies employ either the ubiquitin-proteasome system or the lysosomal degradation system. Here, we report the development of midnolin-based targeting chimeras (MbTACs), a ubiquitin-independent TPD that degrades target proteins. We designed and synthesized peptide-based MbTACs, which are multifunctional molecules containing c-Myc-recognition moieties and midnolin binding moieties. MbTACs promote the formation of a ternary complex consisting of the target protein, MbTACs, and midnolin via chemically induced proximity; subsequently, midnolin recruits the proteasome to degrade the target protein. Biological evaluations demonstrated that the MbTACs could degrade c-Myc effectively through the midnolin-proteasome pathway. The antitumor effects of MbTACs were further validated in vitro and in vivo. Collectively, our results provide a ubiquitin-independent TPD tool. MbTACs represent a conveniently developed modular peptide degradation chimera and have the potential to be widely used in disease therapy. We expect the MbTACs to provide a dimension for TPD design.