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

The Cereblon–G1 to S phase transition 1 (CRBN–GSPT1) complex is a pharmacologically induced protein assembly that facilitates the targeted degradation of GSPT1. Cereblon (CRBN) acts as the substrate receptor for the CRL4 E3 ubiquitin ligase complex, while GSPT1 (also known as eRF3a) is a GTPase involved in translation termination and cell cycle progression [UniProt P15170, Q96SW2]. Small molecule degraders, known as molecular glues, bind to the thalidomide-binding domain of CRBN, altering its surface to create a "neo-degron" binding site for GSPT1 [Matyskiela et al., Nature, 2016]. This recruitment leads to the polyubiquitination of GSPT1 and its subsequent destruction by the 26S proteasome. Because GSPT1 is essential for the survival of certain cancer cells, particularly in acute myeloid leukemia (AML), its targeted degradation via this complex triggers rapid apoptosis [Hansen et al., J Med Chem, 2021]. Clinical development of drugs targeting this complex focuses on hematological malignancies where GSPT1 dependency is high [Surka et al., Blood, 2021].

Other names

Cereblon–eRF3a complexCRBN–eRF3aCRL4(CRBN)–GSPT1 complex

Molecular glue degradation; the drug binds to the Cereblon (CRBN) E3 ligase to induce a neo-protein-protein interaction with GSPT1, leading to GSPT1 ubiquitination and proteasomal degradation.