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

Overview

Authors: Kevin M Cottrell1, Kimberly J Briggs1, Alice Tsai1, Colin Liang1, Patrick McCarren1, Douglas A Whittington1, Minjie Zhang1, Wenhai Zhang1, Alan Huang1, Jannik Andersen1, John P Maxwell1
ORCID iDs: Kevin M Cottrell, Douglas A Whittington, John P Maxwell
  1. Tango Therapeutics, 201 Brookline Ave, Boston, Massachusetts 02215, United States
Institutions: Tango Therapeutics (United States) (United States)
Journal: Journal of medicinal chemistry, volume 69, issue 11, pages 12853-12869
Dates: received 5 January 2026; accepted 16 April 2026; published online 18 May 2026; in print June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1021/acs.jmedchem.6c00035 · PMID 42150143 · PMCID PMC13266975 · OpenAlex W7161581387
Open access: hybrid, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), other condition (population), cellular / molecular (subfield)
MeSH: Antineoplastic Agents*, Brain*, Deoxyadenosines*, Enzyme Inhibitors*, Protein-Arginine N-Methyltransferases*, Purine-Nucleoside Phosphorylase*, Thionucleosides*, Animals, Cell Line, Tumor, Gene Deletion, Humans, Mice, Structure-Activity Relationship (* major topic)
Topic: Cancer-related gene regulation (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Citations: cited by 1 paper (Europe PMC); 28 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Publisher: n/a → American Chemical Society

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 13 MeSH terms, 27 references.

Cite

This paper

Cottrell, K. M., Briggs, K. J., Tsai, A., Liang, C., McCarren, P., Whittington, D. A., Zhang, M., Zhang, W., Huang, A., Andersen, J., & Maxwell, J. P. (2026). The Discovery of TNG456: A Highly Potent, Selective, Brain-Penetrant MTA-Cooperative PRMT5 Inhibitor for the Treatment of <i>MTAP</i>-Deleted Cancers. Journal of medicinal chemistry, 69(11), 12853-12869. https://doi.org/10.1021/acs.jmedchem.6c00035

BibTeX

@article{cottrell2026discovery,
author = {Cottrell, Kevin M and Briggs, Kimberly J and Tsai, Alice and Liang, Colin and McCarren, Patrick and Whittington, Douglas A and Zhang, Minjie and Zhang, Wenhai and Huang, Alan and Andersen, Jannik and Maxwell, John P},
title = {{The Discovery of TNG456: A Highly Potent, Selective, Brain-Penetrant MTA-Cooperative PRMT5 Inhibitor for the Treatment of \<i\>MTAP\</i\>-Deleted Cancers}},
journal = {Journal of medicinal chemistry},
year = {2026},
month = may,
volume = {69},
number = {11},
pages = {12853--12869},
publisher = {American Chemical Society},
issn = {0022-2623},
doi = {10.1021/acs.jmedchem.6c00035},
url = {https://doi.org/10.1021/acs.jmedchem.6c00035},
pmid = {42150143},
pmcid = {PMC13266975}
}

RIS

TY - JOUR
AU - Cottrell, Kevin M
AU - Briggs, Kimberly J
AU - Tsai, Alice
AU - Liang, Colin
AU - McCarren, Patrick
AU - Whittington, Douglas A
AU - Zhang, Minjie
AU - Zhang, Wenhai
AU - Huang, Alan
AU - Andersen, Jannik
AU - Maxwell, John P
TI - The Discovery of TNG456: A Highly Potent, Selective, Brain-Penetrant MTA-Cooperative PRMT5 Inhibitor for the Treatment of <i>MTAP</i>-Deleted Cancers
T2 - Journal of medicinal chemistry
J2 - J Med Chem
PY - 2026
DA - 2026/05/18
VL - 69
IS - 11
SP - 12853
EP - 12869
SN - 0022-2623
PB - American Chemical Society
DO - 10.1021/acs.jmedchem.6c00035
UR - https://doi.org/10.1021/acs.jmedchem.6c00035
LA - en
ER -

CSL-JSON

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