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

This is the authors' abstract. We don't add key points for this paper.

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.