First demonstration of benzosultam CRBN ligand-mediated PROTACs for BTK and BRD4 degradation.

Proteolysis-targeting chimeras (PROTACs) represent a promising therapeutic approach for degrading disease-relevant proteins through the ubiquitin-proteasome system. Among the various E3 ligases employed, cereblon (CRBN) has been the most widely used in PROTAC preparation. However, currently available CRBN ligands often lack sufficient selectivity, as they can trigger off-target protein degradation, such as Sal-like protein 4 (SALL4), which is implicated in teratogenic toxicities. In this study, benzosultam-based CRBN ligands were utilized to prepare PROTACs targeting BRD4 and BTK. Among the PROTACs synthesized, 10a induced efficient degradation of BRD4, while 14a effectively degraded BTK in TMD-8 cells, showing superior or comparable potency to the known compounds ARV-825 and MT-802, respectively. Furthermore, targeted protein degradation translated into potent anti-proliferative activities in TMD-8 cells, with 10a exhibiting robust cell growth inhibition. In contrast to ARV-825 and MT-802, 10a and 14a showed negligible SALL4 degradation, suggesting a favorable off-target safety profile of benzosultam CRBN ligands. These findings underscore the potential of the benzosultam scaffold as a promising and selective alternative for CRBN-mediated targeted protein degradation.