Discovery of novel benzosultam CRBN ligands

Targeted protein degradation (TPD) is a relatively novel drug discovery strategy that could help break through the limitations of traditional small molecule inhibitors. While TPD mostly utilizes diverse E3 ligases to incorporate the ubiquitin-proteasome system (UPS), cereblon (CRBN) could be considered one of the most successfully adopted E3 ligases. Thus, expanding the scope of CRBN ligands has received tremendous attention to overcome related issues, such as selectivity and druggability. In this study, design and synthesis of novel benzosultam-based CRBN ligands have been explored by replacement of lactam in lenalidomide with sultam. The sultam-based ligands showed CRBN binding affinities 2-20 times stronger than lenalidomide, presumably from additional hydrogen bonds generated from the extra oxygen atom in the sultam group, as supported by docking studies. This research highlights the potential of novel benzosultam CRBN ligands as a new tool for CRBN-mediated TPD strategies.