GSPT1

Class

GSPT1 molecular glue degrader (cereblon-based, oral)

Pathway

recruits GSPT1 to the cereblon E3 ubiquitin ligase for targeted proteasomal degradation, selectively killing MYC-driven tumor cells that depend on high GSPT1/translation-termination activity

GSPT1 (also called eRF3a) is a protein that helps terminate translation, the process by which ribosomes read messenger RNA and assemble proteins. When a ribosome reaches a stop codon, GSPT1 works together with release factor eRF1 to end protein synthesis and release the ribosome for reuse. Cells with very high protein synthesis demands, such as those driven by amplified or overactive MYC, a transcription factor that broadly increases ribosome biogenesis and translation, become unusually dependent on efficient translation termination and therefore on GSPT1 activity. This creates a potential vulnerability that can be exploited therapeutically. Rather than inhibiting GSPT1 with a classical enzyme blocker, molecular glue degraders bring GSPT1 into proximity with cereblon, a substrate receptor of an E3 ubiquitin ligase complex normally used by the cell to tag unwanted proteins for destruction. This forces GSPT1 to be ubiquitinated and degraded by the proteasome, the cell's protein-disposal machinery. Because MYC-driven tumor cells rely more heavily on GSPT1 than normal cells, selective degradation can preferentially impair tumor growth. This approach broadly matters in cancers marked by MYC pathway activation, including several solid tumors and hematologic malignancies, where few direct therapies against MYC itself exist.