Cereblon (CRBN)–neosubstrate protein-protein interface (CRBN–neosubstrate PPI)

The Cereblon (CRBN)–neosubstrate protein-protein interface is a pharmacologically induced interaction site formed when a molecular glue degrader binds to the Cereblon E3 ubiquitin ligase (Ito et al., 2010). CRBN is the substrate receptor of the CRL4-CRBN E3 ligase complex, which normally targets specific endogenous proteins for degradation. Small molecules like immunomodulatory imide drugs (IMiDs) bind to the thalidomide-binding domain of CRBN, altering its surface properties to create a "glue" that recruits non-native proteins, known as neosubstrates (Petzold et al., 2016). Common neosubstrates include transcription factors like Ikaros (IKZF1) and Aiolos (IKZF3), or proteins like CK1α and GSPT1, depending on the specific drug (Lu et al., 2014; Kronke et al., 2014). Once recruited to the interface, these neosubstrates are polyubiquitinated and subsequently degraded by the 26S proteasome. This mechanism is central to the therapeutic efficacy of drugs used in treating hematologic malignancies, such as multiple myeloma and myelodysplastic syndromes. Targeting this interface allows for the degradation of previously "undruggable" proteins, though it also carries risks such as teratogenicity and hematologic toxicities.

Other names

CRBN-substrate interfaceCereblon-neosubstrate complexIMiD-induced protein-protein interfaceCereblon-neosubstrate degron interface

Molecular glue-induced recruitment of neosubstrates to the CRL4-CRBN E3 ubiquitin ligase complex, leading to polyubiquitination and subsequent proteasomal degradation (Petzold et al., 2016; Lu et al., 2014).