Discovery of MRT-2359, an orally bioavailable GSPT1 molecular glue degrader

G1 to S phase transition 1 (GSPT1) - also known as eukaryotic release factor 3a (eRF3a) - is a key translation termination factor that helps catalyze the termination of protein synthesis, facilitating the release of mRNA and newly synthesized protein from the ribosomal protein synthesis machinery. We have identified GSPT1 as a potential therapeutic vulnerability for MYC-driven cancers. Molecular glue degraders (MGD) are small molecules able to bind to an E3 ligase such as cereblon (CRBN) and subsequently recruit neosubstrate proteins for ubiquitination-proteasomal degradation. This therapeutic approach shows great potential in treating cancers and other diseases. The focus of the seminar will be MGDs and the discovery of MRT-2359, a potent, selective, and orally bioavailable MGD, able to induce the interaction between CRBN and GSPT1 protein. The compound is currently in a phase 1/2 clinical study for safety, tolerability, and anti-tumor activity evaluation (NCT05546268).