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

The CRBN–GSPT1 interface is a pharmacologically induced protein-protein interaction between the E3 ubiquitin ligase substrate receptor Cereblon (CRBN) and the translation termination factor G1 to S phase transition 1 (GSPT1, also known as eRF3a) (Matyskiela et al., Nature 2016). This interface is not naturally occurring but is stabilized by a class of small molecules known as molecular glues or Cereblon E3 ligase modulators (CELMoDs), such as CC-90009 (Valtematug) (Hansen et al., J. Med. Chem. 2021). When these drugs bind to the thalidomide-binding domain of CRBN, they alter its surface to create a high-affinity docking site for GSPT1 (Surka et al., Blood 2021). The resulting ternary complex facilitates the polyubiquitination of GSPT1 by the CRL4-CRBN E3 ligase complex, leading to its rapid degradation by the 26S proteasome. GSPT1 is essential for the termination of protein synthesis; its depletion triggers an integrated stress response and induces apoptosis, particularly in MYC-driven cancers (Ishizawa et al., Cancer Cell 2019). This target is currently being explored primarily for the treatment of acute myeloid leukemia (AML), where GSPT1 degradation has shown potent anti-leukemic activity in clinical trials (NCT02848001). However, therapeutic application is challenged by potential toxicities such as neutropenia and the development of resistance through mutations in the CRBN-binding pocket or GSPT1 itself.

Other names

CRBN-eRF3a interfaceCereblon-GSPT1 complexCRL4-CRBN-GSPT1 ternary complexCereblon-GSPT1 neo-substrate interface

Molecular glue-induced recruitment of GSPT1 to the CRL4-CRBN E3 ubiquitin ligase complex, leading to polyubiquitination and proteasomal degradation of GSPT1.