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

  • J Med Chem. 2026 Oct 22;69(20):23540-23563. doi: 10.1021/acs.jmedchem.6c00544.
Taiting Shi  1  2 ,  Yuanyuan Pei  2  3 ,  Bo Peng  2 ,  Zerui Wu  1 ,  Yixuan Feng  2  4 ,  Yue Zhao  2 ,  Yangyu Luo  1 ,  Qi Chen  2  4 ,  Songyan Chen  1 ,  Jing Xu  1 ,  Zhuang Shao  2 ,  Yuhang Liu  2 ,  Xueying Gong  2 ,  Shuke Yang  2  4 ,  Xiaoxiao Zou  2 ,  Lixin Zhou  5 ,  Yue Zhao  2 ,  Hewei Jiang  2 ,  Chunlong Xu  2 ,  Zhanchao Meng  2 ,  Wenchao Lu  2 ,  Zhipeng Su  1
Affiliations
  • 1. Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou325000, China.
  • 2. Lingang Laboratory, Shanghai200031, China.
  • 3. School of Physical Science and Technology, ShanghaiTech University, Shanghai201210, China.
  • 4. School of Life Science and Technology, ShanghaiTech University, Shanghai201210, China.
  • 5. Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, China.
PMID: 42911697 DOI: 10.1021/acs.jmedchem.6c00544
Abstract

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.

Keywords
GSPT1; degrader; glioblastoma; molecular glue; phenotypic screening.
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