Ikaros family zinc finger protein 3 (IKZF3)–Cereblon (CRBN)–lenalidomide complex (IKZF3–CRBN–lenalidomide)

The Ikaros family zinc finger protein 3 (IKZF3)–Cereblon (CRBN)–lenalidomide complex is a ternary molecular structure formed when the immunomodulatory drug (IMiD) lenalidomide acts as a molecular glue [PubMed: 24402980]. Lenalidomide binds to the thalidomide-binding domain of CRBN, which is the substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex [UniProt: Q96SW2]. This binding event reconfigures the surface of CRBN, enabling it to recruit the neo-substrate IKZF3 (also known as Aiolos), a transcription factor essential for B-cell development and plasma cell survival [UniProt: Q9UKT9]. Once recruited to the interface, IKZF3 is polyubiquitinated by the E3 ligase complex and subsequently degraded by the 26S proteasome [PubMed: 24402980, 24402981]. The loss of IKZF3 leads to the downregulation of IRF4, a key survival factor in multiple myeloma, thereby exerting a potent anti-proliferative effect on malignant B-cells [PubMed: 24402980]. Additionally, the degradation of IKZF3 in T-cells stimulates the production of interleukin-2 (IL-2), contributing to the immunomodulatory effects of lenalidomide [PubMed: 24402981]. This target interface is a focal point for treating hematologic malignancies and is being explored for autoimmune conditions like systemic lupus erythematosus.

Other names

Aiolos–CRBN–lenalidomide complexIKZF3–Cereblon–IMiD interfaceIKZF3–CRBN–LEN complexCereblon–lenalidomide–IKZF3 ternary complexIKZF3–CRBN–lenalidomide neo-substrate interface

Molecular glue-mediated recruitment of the neo-substrate IKZF3 to the CRL4-CRBN E3 ubiquitin ligase complex, leading to polyubiquitination and proteasomal degradation.