Discovery of LG-NE-29: An Orally Bioavailable GSPT1 Molecular Glue Degrader Effective in Glioblastoma Xenograft Models.

The clinical management of glioblastoma (GBM) is severely hindered by rapid resistance to temozolomide (TMZ). Through viability-based phenotypic screening, we identified the translation termination factor GSPT1 (G1 to S phase transition 1) as a critical vulnerability in GBM cells. Structure-activity relationship optimization of an isoindolinone scaffold, specifically focused on improving metabolic stability, led to the discovery of LG-NE-29, a potent molecular glue degrader. This compound efficiently promotes CRBN-dependent ubiquitination and subsequent proteasomal degradation of GSPT1. LG-NE-29 overcomes the metabolic liabilities of early-generation scaffolds, exhibiting an optimized pharmacokinetic profile highlighted by excellent oral bioavailability (F = 76%). Mechanistically, GSPT1 depletion triggers a profound integrated stress response and intrinsic apoptosis. In U87MG xenograft models, oral administration of LG-NE-29 induced significant tumor regression. Collectively, these findings validate GSPT1 as an actionable therapeutic target in GBM and establish LG-NE-29 as a robust pharmacological tool for further targeted protein degradation research.