Ikaros family zinc finger protein 1–Cereblon–lenalidomide complex (IKZF1–CRBN–LEN)

The Ikaros family zinc finger protein 1 (IKZF1)–Cereblon (CRBN)–lenalidomide neo-substrate interface is a pharmacologically induced molecular complex essential for the therapeutic activity of immunomodulatory imide drugs (IMiDs). In this mechanism, lenalidomide acts as a molecular glue by binding to the thalidomide-binding domain of Cereblon (CRBN), which is the substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex [1, 3]. This binding event reconfigures the surface of CRBN, creating a high-affinity interface for the recruitment of the neo-substrate IKZF1, a zinc-finger transcription factor critical for lymphoid development [2]. Once IKZF1 is recruited to the ligase complex, it undergoes polyubiquitination and subsequent degradation by the 26S proteasome [1, 2]. In multiple myeloma, the loss of IKZF1 leads to the downregulation of essential survival factors like IRF4 and MYC, resulting in cell cycle arrest and apoptosis [2, 4]. This interface is a hallmark of targeted protein degradation (TPD) and serves as a template for the design of novel cereblon-modulating agents [3]. The clinical efficacy of lenalidomide in B-cell malignancies is largely attributed to the formation of this specific ternary complex [1]. Understanding the structural basis of this interface has allowed for the expansion of the molecular glue concept to other E3 ligases and substrates [4]. Citations: [1] Lu, G., et al. (2014). Science, 343(6168), 305-309. [2] Krönke, J., et al. (2014). Science, 343(6168), 301-305. [3] Fischer, E. S., et al. (2014). Nature, 512(7512), 49-53. [4] Petzold, G., et al. (2016). Nature, 529(7586), 333-338.

Other names

IKZF1-CRBN-lenalidomide interfaceIkaros-Cereblon-lenalidomide complexIMiD-induced neo-substrate interfaceLenalidomide-induced IKZF1 degradation complex

Molecular glue-induced targeted protein degradation (TPD)