Lysine-Targeting Covalent Inhibition of Glutaminase Using Cyanopyrimidines.

Authors

Xiwen Xiao, Hibiki Okuno, Saki Inoue, Naoki Zenmyo, Yuya Matsumoto, Emi Mishiro-Sato, Keiko Kano, Kazuaki Yoshimune, Shohei Uchinomiya, Akio Ojida

Published in

JACS Au. Volume 6. Issue 9. Pages 5243-5253. Sep 28, 2026. Epub Sep 03, 2026.

Abstract

Aberrant metabolic activity is a hallmark of cancer and is recognized as a promising target for cancer therapy. However, covalent inhibitors that irreversibly modulate cancer-associated metabolic states remain largely unexplored. Here, we report the development of covalent inhibitors targeting glutaminase 1 (GLS1), a rate-determining enzyme in the glutamine metabolism. To develop covalent inhibitors of GLS1, we systematically evaluated the reactivity of N-heteroaryl nitriles and identified 2-cyanopyrimidine as a lysine-reactive electrophile suitable for selective covalent protein targeting. A covalent inhibitor bearing a 2-cyanopyrimidine irreversibly binds GLS1 in cancer cells with excellent proteome-wide selectivity. This mode of action effectively suppresses glutamine metabolism and induces death of glutamine-dependent cancer cells, highlighting the therapeutic potential of covalent targeting of GLS1.

PMID:
42819310
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

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