Cereblon–G1 to S phase transition 1 neo-substrate complex (CRBN–GSPT1 complex)

The CRBN–GSPT1 neo-substrate complex is a ternary protein-drug assembly formed when a molecular glue degrader, such as a cereblon E3 ligase modulating drug (CELMoD), bridges the interaction between the E3 ubiquitin ligase substrate receptor Cereblon (CRBN) and the translation termination factor G1 to S phase transition 1 (GSPT1). GSPT1, also known as eRF3a, is not a natural substrate of CRBN; however, the presence of specific small molecules reshapes the CRBN surface to recognize a structural degron (G-loop) on GSPT1. This recruitment leads to the polyubiquitination and rapid proteasomal degradation of GSPT1, which is essential for protein synthesis and cell cycle progression. In therapeutic contexts, targeting this complex is particularly effective in MYC-driven malignancies and hematological cancers like acute myeloid leukemia (AML), where cells exhibit a high dependency on efficient translation. The depletion of GSPT1 triggers the integrated stress response (ISR) and induces apoptosis, even in TP53-mutant cells. While highly potent, drugs targeting this complex must be carefully designed to avoid off-target degradation of other CRBN-sensitive proteins like Ikaros (IKZF1) and Aiolos (IKZF3) to manage systemic toxicity and improve the therapeutic window.

Other names

CRBN–eRF3a complexCereblon–eRF3a complexCRL4(CRBN)–GSPT1 complexCRBN–GSPT1 ternary complex

Molecular glue-induced degradation where a small molecule (CELMoD) binds to the Cereblon (CRBN) E3 ligase and recruits the neo-substrate GSPT1, leading to its ubiquitination and subsequent proteasomal degradation.