Cereblon–G1 to S phase transition 1 ternary complex (CRBN–GSPT1 complex)

The Cereblon–G1 to S phase transition 1 (CRBN–GSPT1) ternary complex is a molecular assembly induced by specific molecular glue degraders, such as CC-90009, which bridge the E3 ubiquitin ligase substrate receptor Cereblon (CRBN) and the translation termination factor GSPT1 (also known as eRF3a) [PMID: 33432168]. In this complex, the small molecule occupies the surface of CRBN, creating a new interface that binds with high affinity to the GSPT1 protein, a neosubstrate that CRBN does not naturally recognize [PMID: 27338790]. This interaction leads to the polyubiquitination of GSPT1 by the CRL4-CRBN E3 ligase complex and its subsequent degradation by the 26S proteasome [PMID: 33432168]. GSPT1 is critical for protein synthesis and cell cycle progression, and its rapid depletion is particularly lethal to acute myeloid leukemia (AML) cells, which exhibit a high dependency on this factor [PMID: 33432168, PMID: 34161563]. Consequently, the formation of this ternary complex is a primary therapeutic strategy for treating hematologic malignancies by exploiting the targeted protein degradation (TPD) pathway. The clinical development of drugs targeting this complex must balance potent anti-leukemic activity with potential toxicities, such as neutropenia, resulting from GSPT1 degradation in healthy hematopoietic cells [PMID: 33432168].

Other names

CRBN-GSPT1 complexCRBN-eRF3a complexCereblon-GSPT1 complexCRL4-CRBN-GSPT1 complex

Molecular glue-mediated targeted protein degradation (TPD) leading to polyubiquitination and proteasomal degradation of GSPT1.