Cereblon (CRBN)–G1 to S phase transition 1 (GSPT1)–NIMA-related kinase 7 (NEK7)–Sal-like protein 4 (SALL4) neo-substrate complex (CRBN–GSPT1–NEK7–SALL4)

The Cereblon (CRBN)–G1 to S phase transition 1 (GSPT1)–NIMA-related kinase 7 (NEK7)–Sal-like protein 4 (SALL4) neo-substrate complex is a multi-protein assembly formed when molecular glue degraders recruit non-native substrates to the CRL4-CRBN E3 ubiquitin ligase. These neo-substrates share a common structural recognition motif, typically a glycine-rich loop (G-loop) or a specific zinc-finger fold, which allows them to bind the CRBN surface in the presence of small molecules like thalidomide analogs or CC-90009 (Matyskiela et al., 2018; Kozicka et al., 2023). Once the ternary complex is formed, the neo-substrate is polyubiquitinated and subsequently degraded by the 26S proteasome. This mechanism is leveraged in oncology, where the degradation of GSPT1 by CC-90009 induces apoptosis in acute myeloid leukemia (AML) cells (Surka et al., 2021). Additionally, the degradation of NEK7 is being explored as a therapeutic strategy to inhibit the NLRP3 inflammasome in inflammatory diseases. However, the recruitment of SALL4 is primarily associated with the teratogenic side effects of thalidomide, making it a critical off-target to avoid in drug development (Donovan et al., 2018). The study of this complex is central to the field of targeted protein degradation (TPD) and the design of highly selective molecular glues.

Other names

CRBN-mediated neo-substrate complexG-loop neo-substrate complexCRL4-CRBN-substrate complexCereblon-GSPT1-NEK7-SALL4 complex

Molecular glue-induced recruitment of neo-substrates to the CRL4-CRBN E3 ubiquitin ligase complex, leading to polyubiquitination and subsequent proteasomal degradation.