Cereblon within the Cullin-RING ligase 4 E3 ubiquitin ligase complex (CRL4-CRBN)

Cereblon (CRBN) is the substrate recognition component of the Cullin-RING ligase 4 (CRL4) E3 ubiquitin ligase complex, which also includes CUL4, DDB1, and RBX1 [1, 3]. It plays a critical role in cellular protein homeostasis by targeting specific substrates for polyubiquitination and subsequent proteasomal degradation [2, 6]. CRBN is the primary molecular target of immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide [5, 11]. These drugs act as "molecular glues," binding to the CRBN pocket and altering its substrate specificity to induce the degradation of non-physiological "neosubstrates," including transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos), which are essential for the survival of multiple myeloma cells [1, 8]. Beyond its role in cancer therapy, CRBN is involved in physiological processes like limb development and neuronal function; its modulation by thalidomide is responsible for the drug's notorious teratogenic effects [6, 12]. Additionally, CRBN is widely utilized in the design of Proteolysis Targeting Chimeras (PROTACs) to achieve targeted degradation of otherwise undruggable proteins [8, 12].

Other names

CRBNMRT2MRT2ACereblonCRL4-CRBN complexDDB1-CUL4-ROC1-CRBN complex

Molecular glue degradation of neosubstrates (e.g., IKZF1, IKZF3, CK1α) and E3 ligase recruitment for targeted protein degradation (PROTACs).