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

Journal of Medicinal Chemistry 2026 Open access

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Authors: Kevin M. Cottrell, Kimberly J. Briggs, Alice Tsai, Colin Liang, Patrick McCarren, Douglas A. Whittington, Minjie Zhang, Wenhai Zhang, Alan Huang, Jannik Andersen, John P. Maxwell
DOI: 10.1021/acs.jmedchem.6c00035
Cited by: 1
References: 27

Abstract

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.

Fields of Study & Subjects

Cancer-related gene regulation Blood Coagulation and Thrombosis Mechanisms Nuclear Receptors and Signaling

Publication details

Journal / source
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Volume
69
Issue
11
Pages
12853–12869
Publication date
18 May 2026
Language
EN