Casein kinase 1 alpha – Cereblon – lenalidomide complex (CK1α–CRBN–lenalidomide)

The Casein kinase 1 alpha – Cereblon – lenalidomide complex is a ternary molecular assembly that mediates the therapeutic effects of lenalidomide in specific hematologic malignancies. Lenalidomide functions as a molecular glue by binding to the Cereblon (CRBN) subunit of the CRL4-CRBN E3 ubiquitin ligase complex, which redefines the ligase's substrate specificity (Krönke et al., 2015; Fischer et al., 2014). This binding event creates a novel protein-protein interface (the neo-substrate interface) that specifically recruits Casein kinase 1 alpha (CK1α), a serine/threonine kinase involved in cell cycle regulation and Wnt signaling (Petzold et al., 2016). Once recruited, CK1α undergoes polyubiquitination and is subsequently degraded by the 26S proteasome. This targeted degradation is particularly lethal to cells with a deletion of chromosome 5q (del(5q) myelodysplastic syndrome), as these cells are haploinsufficient for the CSNK1A1 gene and are highly sensitive to further reduction in CK1α protein levels (Krönke et al., 2015). The resulting depletion of CK1α triggers p53-dependent apoptosis, selectively eliminating the malignant del(5q) clone while sparing normal hematopoietic stem cells. This mechanism represents a landmark in the field of targeted protein degradation, demonstrating how small molecules can reprogram E3 ligases to eliminate disease-relevant proteins that were previously considered undruggable.

Other names

CK1α–CRBN–IMiD interfaceCereblon–CK1α neo-substrate complexCRL4-CRBN-lenalidomide-CK1α complexLenalidomide-induced CK1α-CRBN complex

Molecular glue-induced targeted protein degradation