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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.<\/jats:p>","DOI":"10.1021\/jacsau.6c00924","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T20:46:55Z","timestamp":1788468415000},"page":"5243-5253","source":"Crossref","is-referenced-by-count":0,"title":["Lysine-Targeting Covalent Inhibition of Glutaminase\nUsing Cyanopyrimidines"],"prefix":"10.1021","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1660-3604","authenticated-orcid":true,"given":"Xiwen","family":"Xiao","sequence":"first","affiliation":[{"name":"Kyushu University , , 3-1-1 Maidashi, Higashi-ku , ,","place":["Fukuoka, Japan, 812-8582"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hibiki","family":"Okuno","sequence":"additional","affiliation":[{"name":"Kyushu University , , 3-1-1 Maidashi, Higashi-ku , ,","place":["Fukuoka, Japan, 812-8582"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saki","family":"Inoue","sequence":"additional","affiliation":[{"name":"Kyushu University , , 3-1-1 Maidashi, Higashi-ku , ,","place":["Fukuoka, Japan, 812-8582"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Zenmyo","sequence":"additional","affiliation":[{"name":"Kyushu University , , 3-1-1 Maidashi, Higashi-ku , ,","place":["Fukuoka, Japan, 812-8582"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Kyushu University , , 3-1-1 Maidashi, Higashi-ku , ,","place":["Fukuoka, Japan, 812-8582"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emi","family":"Mishiro-Sato","sequence":"additional","affiliation":[{"name":"Nagoya University , , Furo-Cho, Chikusa-ku , ,","place":["Nagoya, Japan, 464-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Kano","sequence":"additional","affiliation":[{"name":"Nagoya University , , Furo-Cho, Chikusa-ku , ,","place":["Nagoya, Japan, 464-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuaki","family":"Yoshimune","sequence":"additional","affiliation":[{"name":"Nihon University , , Izumi-cho 1-2-1 , , ,","place":["Narashino, Chiba, Japan, 275-8575"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Uchinomiya","sequence":"additional","affiliation":[{"name":"Kyushu University , , 3-1-1 Maidashi, Higashi-ku , ,","place":["Fukuoka, Japan, 812-8582"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9440-8167","authenticated-orcid":true,"given":"Akio","family":"Ojida","sequence":"additional","affiliation":[{"name":"Kyushu University , , 3-1-1 Maidashi, Higashi-ku , ,","place":["Fukuoka, Japan, 812-8582"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"issue":"8","key":"2026092808085973200_cit1","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1016\/j.cell.2023.01.038","article-title":"What\nis cancer metabolism?","volume":"186","author":"Finley","year":"2023","journal-title":"Cell"},{"issue":"8","key":"2026092808085973200_cit2","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1016\/j.cmet.2023.07.006","article-title":"Emerging\ntherapies in cancer metabolism","volume":"35","author":"Xiao","year":"2023","journal-title":"Cell Metab."},{"issue":"4","key":"2026092808085973200_cit3","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1038\/s12276-023-00971-9","article-title":"Targeting glutamine\nmetabolism as a therapeutic strategy for cancer","volume":"55","author":"Jin","year":"2023","journal-title":"Exp. 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Cancer Ther."},{"issue":"23","key":"2026092808085973200_cit34","doi-asserted-by":"publisher","first-page":"10551","DOI":"10.1021\/jm301191p","article-title":"Design,\nsynthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl\nsulfide 3 (BPTES) analogs as glutaminase inhibitors","volume":"55","author":"Shukla","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026092808085973200_cit35","first-page":"451","article-title":"Selective Inhibition of Glutaminase by Bis-Thiadiazoles","volume":"6","author":"Newcomb","year":"2002","journal-title":"U.S. Patent"},{"issue":"2","key":"2026092808085973200_cit36","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1021\/acschembio.2c00633","article-title":"Profiling\nsulfur (VI) fluorides as reactive functionalities for chemical biology\ntools and expansion of the ligandable proteome","volume":"18","author":"Gilbert","year":"2023","journal-title":"ACS Chem. 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