Development of Phenyl-substituted Isoindolinone- and Benzimidazole-type Cereblon Ligands for Targeted Protein Degradation

Thalidomide, pomalidomide and lenalidomide, collectively referred to as immunomodulatory imide drugs (IMiDs), are frequently employed in proteolysis-targeting chimeras (PROTACs) as cereblon (CRBN) E3 ligase-recruiting ligands. However, their molecular glue properties that co-opt the CRL4CRBN to degrade its non-natural substrates may lead to undesired off-target effects for the IMiD-based PROTAC degraders. Herein, we reported a small library of potent and cell-permeable CRBN ligands, which exert high selectivity over the well-known CRBN neo-substrates of IMiDs by structure-based design. They were further utilized to construct bromodomain-containing protein 4 (BRD4) degraders, which successfully depleted BRD4 in the tested cells. Overall, we reported a series of functionalized CRBN recruiters that circumvent the promiscuity from traditional IMiDs, and this study is informative to the development of selective CRBN-recruiting PROTACs for many other therapeutic targets. A small library of compounds based on isoindolinone or 2,3-dihydro-2-oxo-1H-benzimidazole were constructed as potential cereblon binders. Their activity was explored using cell-based and biochemical binding assays. Several potent, selective, and cell-permeable CRBN ligands were identified. A potent BRD4 degrader was successfully developed from the 2,3-dihydro-2-oxo-1H-benzimidazole-derived ligand, suggesting the potential for these ligands to develop PROTAC degraders against many other therapeutic targets.+image