Rational design and synthesis of a novel cereblon ligand class enabling selective molecular glue and potent PROTAC

The expansion of E3 ligands provides elemental value for the research and drug design of both molecular glues and proteolysis-targeting chimeras (PROTAC). This study first reports the rational design of a novel class of sulfur-incorporated CRBN ligands (SCLs) with enhanced binding affinity over classical immunomodulatory drugs (IMiDs). Based on this platform, we developed: (1) GT-02624, a GSPT1 molecular glue degrader with small size, degradation selectivity among the tested canonical CRBN neosubstrates and corresponding anti-proliferative activity; and (2) GT-01956, a BET-targeting PROTAC exhibiting picomolar degradation potency and exceptional anti-proliferative activity across hematologic and solid tumor cell lines. GT-01956 showed no off-target degradation of GSPT1 and outperformed nitrogen/oxygen-substituted analogs, underscoring the critical role of sulfur. Our work establishes SCLs as a superior platform for discovering precision protein degraders with high potency and selectivity, which may, in future, accelerate the development of molecular glue and PROTAC candidates.