The Discovery of TNG456: A Highly Potent, Selective, Brain-Penetrant MTA-Cooperative PRMT5 Inhibitor for the Treatment of MTAP-Deleted Cancers

  • J Med Chem. 2026 Jun 11;69(11):12853-12869. doi: 10.1021/acs.jmedchem.6c00035.
Kevin M Cottrell  1 ,  Kimberly J Briggs  1 ,  Alice Tsai  1 ,  Colin Liang  1 ,  Patrick McCarren  1 ,  Douglas A Whittington  1 ,  Minjie Zhang  1 ,  Wenhai Zhang  1 ,  Alan Huang  1 ,  Jannik Andersen  1 ,  John P Maxwell  1
Affiliations
  • 1. Tango Therapeutics, 201 Brookline Ave, Boston, Massachusetts 02215, United States.
PMID: 42150143 DOI: 10.1021/acs.jmedchem.6c00035
Abstract

Homozygous deletion of the methylthioadenosine Phosphorylase (MTAP) gene occurs in 10-15% of all human cancers and up to 50% of high-grade malignant gliomas, representing one of the largest opportunities for precision oncology. Loss of MTAP leads to the accumulation of 5'-methylthioadenosine (MTA), which sensitizes tumor cells to inhibition of protein arginine methyltransferase 5 (PRMT5). Herein we describe the discovery of TNG456, a potent and highly selective MTA-cooperative PRMT5 Inhibitor that is brain penetrant in preclinical species and currently in Phase I/II clinical studies for the treatment of advanced or metastatic solid tumors with MTAP loss, with a focus on glioblastoma.

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