Identification of potent and orally bioavailable GSPT1 molecular glue degraders

  • Bioorg Med Chem Lett. 2025 Dec 15:129:130375. doi: 10.1016/j.bmcl.2025.130375.
Run-Duo Gao  1 ,  Wenzhong Liu  2 ,  Yuanyuan Liu  2 ,  Grace Xie  3 ,  Haotian Fang  2 ,  Xingxing Xu  2 ,  Meilu Yan  2 ,  Shu-Li You  4
Affiliations
  • 1. Wigen Biomedicine Technology (Shanghai) Co., Ltd, No. 2, Lane 720, Cailun Road, Shanghai 201210, China. Electronic address: [email protected].
  • 2. Wigen Biomedicine Technology (Shanghai) Co., Ltd, No. 2, Lane 720, Cailun Road, Shanghai 201210, China.
  • 3. Shanghai High School International Division, 400 Shangzhong Road, Shanghai 200231, China.
  • 4. New Cornerstone Science Laboratory, State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China.
PMID: 40825410 DOI: 10.1016/j.bmcl.2025.130375
Abstract

G1 to S phase transition 1 (GSPT1) is involved in multiple biological processes and is significantly overexpressed in various Cancer tissues and cells. Degradation of GSPT1 protein proves to be a potential therapeutic option through the technology of molecular glue, however, no molecules have been approved for clinical use. Here, we report our efforts on Structure-Activity Relationship studies around an innovative tricyclic-containing derivatives as potent and orally bioavailable GSPT1 degraders. An in vivo xenograft model study showed that one of the synthesized compounds (26) effectively suppressed NCI-N87 tumor growth, suggesting a direction in the development of novel GSPT1 degraders.

Keywords
GSPT1; Molecular glue; Targeted protein degradation.
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