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However, the development of ALKBH5 inhibitors is slow compared to FTO inhibitors. Inspired by a non\u2010catalytic C200\u2010covalent strategy, a series of maleimide derivatives were designed and synthesized as potent and covalent ALKBH5 inhibitors in this work. The analog\n                    <jats:bold>18<\/jats:bold>\n                    \u2009\n                    <jats:bold>l<\/jats:bold>\n                    exhibited excellent inhibitory effects on ALKBH5 (IC\n                    <jats:sub>50<\/jats:sub>\n                    =0.62\u2005\u03bcM), and exerted a strong antiproliferative effect on NB4 cells with IC\n                    <jats:sub>50<\/jats:sub>\n                    of 0.63\u2005\u03bcM. The\n                    <jats:italic>\n                      K\n                      <jats:sub>d<\/jats:sub>\n                    <\/jats:italic>\n                    value of\n                    <jats:bold>18<\/jats:bold>\n                    \u2009\n                    <jats:bold>l<\/jats:bold>\n                    binding to ALKBH5 was 804\u2005nM, while no binding was observed with FTO. This result indicated that\n                    <jats:bold>18<\/jats:bold>\n                    \u2009\n                    <jats:bold>l<\/jats:bold>\n                    was a highly selective inhibitor of ALKBH5 rather than FTO. Additionally, proteomic experiments showed that\n                    <jats:bold>18<\/jats:bold>\n                    \u2009\n                    <jats:bold>l<\/jats:bold>\n                    directly targeted ALKBH5 in cells and altered m\n                    <jats:sup>6<\/jats:sup>\n                    A levels on mRNA, blocked the related downstream signal pathways, promoted differentiation, and induced apoptosis. Furthermore,\n                    <jats:bold>18<\/jats:bold>\n                    \u2009\n                    <jats:bold>l<\/jats:bold>\n                    exerted excellent\n                    <jats:italic>in vivo<\/jats:italic>\n                    antitumor activity with TGI\n                    <jats:sub>TV<\/jats:sub>\n                    values of 66.3\u2009% at 1\u2005mg\/kg in NB4 tumor xenograft models.\n                  <\/jats:p>","DOI":"10.1002\/anie.202424928","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T05:46:06Z","timestamp":1740030366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Discovery of Covalent and Cell\u2010Active ALKBH5 Inhibitors with Potent Antileukemia Effects\n                    <i>In Vivo<\/i>"],"prefix":"10.1002","volume":"64","author":[{"given":"Hengbo","family":"Wu","sequence":"first","affiliation":[{"name":"State Key Laboratory 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