Cereblon (CRBN) as part of the CRL4-CRBN E3 ubiquitin ligase complex (CRL4-CRBN)

Cereblon (CRBN) serves as the substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex, which also includes Cullin-4 (CUL4A or CUL4B), DNA damage-binding protein 1 (DDB1), and Regulator of Cullins 1 (RBX1). In its physiological state, CRBN facilitates the ubiquitination and subsequent proteasomal degradation of specific endogenous proteins involved in cell cycle regulation and ion channel proteostasis (UniProt P50198). The complex is the primary target for immunomodulatory imide drugs (IMiDs) like thalidomide and lenalidomide, which bind to a hydrophobic pocket in CRBN to redirect the ligase's activity toward non-native substrates, known as neo-substrates. This drug-induced degradation of transcription factors like Ikaros and Aiolos is particularly effective in treating hematologic malignancies such as multiple myeloma, as it leads to the inhibition of tumor cell growth and modulation of the immune response (Chamberlain et al., 2014). Beyond oncology, the CRL4-CRBN complex is a foundational tool in the development of PROTAC technology, where it is harnessed to selectively degrade a wide variety of disease-causing proteins.

Other names

CRBNCullin-4 RING E3 ubiquitin ligase complexCRL4-CRBN E3 ligaseCereblon-DDB1-CUL4A-RBX1 complexProtein cereblon

Drugs targeting this complex act as molecular glues or PROTACs (Proteolysis Targeting Chimeras). Immunomodulatory imide drugs (IMiDs) bind to the cereblon subunit, altering its substrate specificity to recruit and ubiquitinate 'neo-substrates' such as Ikaros (IKZF1) and Aiolos (IKZF3) for proteasomal degradation (Ito et al., 2010; Fischer et al., 2014).