[Cereblon as a primary target of IMiDs]

Various derivatives of thalidomide, a drug that is well-known for its teratogenicity, have recently been developed; among them, lenalidomide and pomalidomide, known as immunomodulatory drugs (IMiDs), have potent anticancer activity. These drugs have been approved by Food and Drug Administration for the treatment of several diseases, including multiple myeloma, under strict control. The primary direct target protein of thalidomide and IMiDs is cereblon (CRBN), a substrate receptor of Cullin-RING ligase 4 (CRL4). CRL4^CRBN is a unique E3 ubiquitin ligase because its substrate selectivity is altered by ligands such as IMiDs. Each IMiD induces degradation of neosubstrates, such as Ikaros or CK1a. Because the activity of new CRBN-binding compounds is not limited to immunomodulation, the designation of "cereblon modulators" has been proposed for these small CRBN-binding compounds. Currently, researchers are investigating CC-122 (avadomide) and CC-220 (iberdomide) for the treatment of diffuse large B-cell lymphoma and systemic lupus erythematosus, respectively. Other recent studies have been investigating heterobifunctional molecules called proteolysis-targeting chimeras (PROTACs) for protein of interest degradation. Moreover, several proteins, such as BRD4, CDK9, or Tau, have already been successfully degraded by CRBN-based PROTACs. In this review, recent advances in CRBN and its binding compounds have been discussed.