Protein cereblon (CRBN)

Protein cereblon (CRBN) is a substrate receptor that functions as a critical component of the CRL4-CRBN E3 ubiquitin ligase complex, which also includes DDB1, Cullin-4, and RBX1 [1, 8, 15]. Its primary biological role involves the recruitment of specific proteins for ubiquitination and subsequent degradation by the proteasome, thereby regulating processes such as embryonic limb development, ion channel activity, and cellular metabolism [4, 13, 16]. CRBN is the primary molecular target for immunomodulatory imide drugs (IMiDs) like thalidomide, lenalidomide, and pomalidomide, which are used to treat hematologic malignancies such as multiple myeloma and myelodysplastic syndromes [3, 7, 10]. These drugs function as molecular glues, altering the substrate specificity of the E3 ligase to induce the degradation of neosubstrates like the transcription factors Ikaros and Aiolos [6, 17, 20]. Beyond its role in cancer, mutations in the CRBN gene are associated with autosomal recessive intellectual disability [1, 4]. However, the therapeutic use of CRBN-targeting agents is constrained by significant safety concerns, most notably the risk of severe teratogenicity linked to the degradation of unintended substrates like SALL4 [18]. CRBN is also a central component in the development of proteolysis-targeting chimeras (PROTACs), where it serves as the E3 ligase recruiter for the degradation of diverse proteins of interest [4, 12].

Other names

CRBNMRT2MRT2A

Drugs targeting Cereblon typically act as molecular glues that redefine the substrate binding surface of the CRL4-CRBN E3 ligase complex, enabling the recruitment and ubiquitination of neosubstrates such as IKZF1, IKZF3, and CK1alpha [3, 6, 15]. Additionally, Cereblon serves as an E3 ligase recruiter for heterobifunctional PROTAC molecules [4, 12].