Cereblon-based E3 ubiquitin ligase complex (CRL4-CRBN)

The Cereblon-based E3 ubiquitin ligase complex (CRL4-CRBN) is a multi-component enzyme assembly comprising the substrate receptor Cereblon, the adapter protein DDB1, the scaffold protein Cullin-4 (CUL4A or CUL4B), and the RING-finger protein RBX1 [1][2]. It functions within the ubiquitin-proteasome system to catalyze the polyubiquitination of specific proteins, thereby signaling their degradation by the 26S proteasome [3]. While its endogenous substrates include proteins involved in DNA repair and homeostatic regulation, the complex is most notable for its interaction with immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide [4]. These drugs function as molecular glues that bind to a hydrophobic pocket in Cereblon, altering its surface to facilitate the recruitment and degradation of neo-substrates like the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) [5]. This mechanism is highly effective in treating hematological cancers, particularly multiple myeloma, where the degradation of these factors leads to cell cycle arrest and apoptosis [6]. Additionally, the CRL4-CRBN complex is a foundational tool in the development of Proteolysis Targeting Chimeras (PROTACs), which leverage the complex's degradation machinery to target a wide array of previously undruggable proteins [7].

Other names

CRBN-CRL4 complexCullin-4-RING E3 ubiquitin ligase complexCRL4(CRBN) E3 ubiquitin ligaseCereblon-DDB1-CUL4A-RBX1 complex

Molecular glue-mediated recruitment of neo-substrates for ubiquitination and subsequent proteasomal degradation; Targeted protein degradation (TPD) via PROTAC recruitment