G1 to S phase transition 1 (GSPT1) is a key translation termination factor that significantly overexpressed in various cancer tissues and cells. Molecular glue is a kind of small molecule, which can bind to an E3 ligase such as cereblon (CRBN) and subsequently recruit neosubstrate proteins for ubiquitination-proteasomal degradation. This emerging therapeutic approach shows great potential in treating cancers and other diseases. This review aims to introduce current understanding of antitumor mechanism of molecular glues targeting GSPT1, summarize pharmacology profiles of existing molecular glues, and outline development strategies of novel molecular glues. The insights provided in this review will be valuable for future studies.

The eukaryotic class II polypeptide chain release factor (eRF3) is an eRF1- and ribosome-dependent GTPase involved in translation termination of protein biosynthesis. eRF3 is a multifunctional protein that is also involved in chromosomal segregation and cytokinesis during mitosis. Survivin is a member of the inhibitor of apoptosis protein (IAP) family that is involved in the organisation of spindle and cell apoptosis. Interaction between survivin and eRF3a-F3 or eRF3b, encoded by the GSPT1 and GSPT2 genes, respectively, was confirmed using yeast two-hybrid (Y2H) and pull-down assays in vitro, and co-immunoprecipitation in vivo. The domains involved in the formation of the survivin-eRF3s complex have been identified. The sites on survivin that interact with eRF3 are located in the baculovirus IAP repeat domain (residues 65-76), which forms a beta-strand structure with an overall negative charge. The sites on eRF3 that interact with survivin were localised to the N-terminal domain(NTD; residues 131-200). Cell localisation experiments indicate that both factors are in the nucleus, suggesting that they cooperatively function in nuclear processes.