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

Abstract 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.