Cereblon-DDB1-CUL4-ROC1 E3 ubiquitin ligase complex (CRL4-CRBN) (CRL4-CRBN)

The Cereblon-DDB1-CUL4-ROC1 E3 ubiquitin ligase complex (CRL4-CRBN) is a multi-subunit enzyme belonging to the Cullin-4-RING ligase family, where Cereblon (CRBN) serves as the substrate-binding receptor [1, 2]. The complex is composed of CRBN, the adaptor protein Damage-specific DNA binding protein 1 (DDB1), a Cullin scaffold (CUL4A or CUL4B), and the RING-finger protein ROC1 (RBX1) [3]. Its primary biological role involves the polyubiquitination of specific proteins, marking them for degradation by the 26S proteasome [4]. This complex is the molecular target for immunomodulatory imide drugs (IMiDs), which bind to the thalidomide-binding domain of CRBN [5]. Binding of these drugs alters the surface of CRBN, allowing it to recruit neo-substrates such as the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) that are not normally targeted [6]. The degradation of these substrates leads to the anti-proliferative and pro-apoptotic effects observed in hematologic malignancies like multiple myeloma [7]. Beyond its role in cancer, mutations in the CRBN component are associated with autosomal recessive intellectual disability [8]. The complex is also a central tool in the development of Proteolysis Targeting Chimeras (PROTACs), which utilize CRBN to induce the degradation of various pathogenic proteins [9]. Safety concerns associated with targeting this complex include significant teratogenicity and myelosuppression [10].

Other names

CRL4-CRBN complexCRBN-DDB1-CUL4A-RBX1 complexCereblon-containing E3 ubiquitin ligase complexCRL4-CRBN E3 ligase

Drugs targeting this complex primarily act as molecular glues that reprogram the substrate specificity of the Cereblon subunit, leading to the recruitment, ubiquitination, and proteasomal degradation of neo-substrates such as Ikaros and Aiolos [5, 6]. Additionally, the complex is utilized by Proteolysis Targeting Chimeras (PROTACs) to induce the degradation of specific proteins of interest by bringing them into proximity with the E3 ligase [9].