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The methyltransferase METTL9 acts as an important enzyme catalyzing 1\u2010MH of histidine in diverse protein substrates, with mounting evidence suggesting its involvement in tumor progression. Despite its potential significance, no inhibitors targeting METTL9 have been previously identified. Here, we introduce compound\n                    <jats:bold>METTL9i<\/jats:bold>\n                    as a first\u2010in\u2010class, highly potent, and selective METTL9 inhibitor.\n                    <jats:bold>METTL9i<\/jats:bold>\n                    inhibits METTL9 with a half\u2010maximum inhibitory concentration (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) of 0.067\u00a0\u00b1\u00a00.009\u00a0\u00b5M and exhibits selectivity over other methyltransferases. Structural analysis via crystallography reveals that\n                    <jats:bold>METTL9i<\/jats:bold>\n                    binds within the S\u2010adenosylmethionine (SAM) binding pocket. In cells,\n                    <jats:bold>METTL9i<\/jats:bold>\n                    engages METTL9 and leads to a reduction in global 1\u2010MH levels. These results support\n                    <jats:bold>METTL9i<\/jats:bold>\n                    as a useful tool compound for investigating METTL9 biology and the functions of histidine 1\u2010MH, while also serving as a promising lead compound for drug discovery targeting METTL9.\n                  <\/jats:p>","DOI":"10.1002\/anie.3642560","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:09:22Z","timestamp":1774271362000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Discovery of a Potent and Selective Cell\u2010Active Inhibitor of Histidine\u2010N1 Methyltransferase METTL9"],"prefix":"10.1002","volume":"65","author":[{"given":"Rui","family":"Yao","sequence":"first","affiliation":[{"name":"Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University  Chengdu Sichuan China"},{"name":"New Cornerstone Science Laboratory 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