2. Academic Validation
  3. Structure-based discovery of a highly potent, selective, and brain-penetrant MTA-cooperative PRMT5 synthetic lethal inhibitor for the treatment of glioblastoma

Structure-based discovery of a highly potent, selective, and brain-penetrant MTA-cooperative PRMT5 synthetic lethal inhibitor for the treatment of glioblastoma

  • Eur J Med Chem. 2026 Oct 5:315:119001. doi: 10.1016/j.ejmech.2026.119001.
Bang Li 1,  Xingcan Wang 2,  Jinqi Yu 1,  Qinfa Xie 1,  Qiongyu Shi 3,  Shuxian Li 3,  Meiyu Geng 4,  Xun Huang 5,  Yuanxiang Wang 6,  Hong Yang 7
Affiliations

Affiliations

  • 1 Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
  • 2 Lingang Laboratory, Shanghai, 200031, China; Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 3 Lingang Laboratory, Shanghai, 200031, China.
  • 4 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 5 Lingang Laboratory, Shanghai, 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 6 Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China; State Key Laboratory of Anti-Infective Drug Development, Guangzhou, 510006, China. Electronic address: [email protected].
  • 7 Lingang Laboratory, Shanghai, 200031, China. Electronic address: [email protected].
PMID: 42190431 DOI: 10.1016/j.ejmech.2026.119001
Abstract

The PRMT5·MTA complex has been recognized as a potential drug target for the treatment of MTAP-deleted cancers, especially for the brain tumors. Although several MTA-cooperative PRMT5 synthetic lethal inhibitors have been advanced into clinical trials, only one of them (TNG908) showed brain permeability in the preclinical evaluation but failed to achieve the anticipated therapeutic exposure levels in glioblastoma in clinical trials. In this study, we reported the discovery of compound 21, which showed much higher brain permeability than TNG908. More importantly, compound 21 achieved significant tumor growth inhibition in an orthotopic U87MG brain tumor model, supported by its enhanced distribution and penetration within brain tissue. These results indicate the potential clinical advantages of compound 21 for treating MTAP- deleted tumors and support its potential utility against intracranial malignancies.

Keywords

Glioblastoma; MTA-Cooperative PRMT5; Synthetic lethal.

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