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Consequently, targeted inhibition of human mitochondrial RNA polymerase (POLRMT) to block mitochondrial gene expression emerges as a novel potential strategy for treating AML through OXPHOS modulation. In this study, based on the previously reported crystal structure of the POLRMT inhibitor IMT1B, we employed a scaffold hopping strategy to design and synthesize a series of derivatives featuring additional hydrophobic occupying groups. A new potent POLRMT inhibitor (<jats:bold>10a<\/jats:bold>) was discovered, which displayed potent antiproliferative activity and could disrupt mitochondrial function and induce apoptosis in MOLM\u201013 cells. Together, these results demonstrate that <jats:bold>10a<\/jats:bold> is a new POLRMT inhibitor, which may provide a candidate lead for AML treatment.<\/jats:p>","DOI":"10.1111\/cbdd.70127","type":"journal-article","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T10:24:30Z","timestamp":1748168670000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis and Biological Evaluation of <scp>POLRMT<\/scp> Inhibitors for the Treatment of Acute Myeloid Leukemia"],"prefix":"10.1111","volume":"105","author":[{"given":"Tianli","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University  Shihezi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoling","family":"Cheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University  Shihezi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yupeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University  Shihezi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenli","family":"Hao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University  Shihezi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hangyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University  Shihezi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2509-9636","authenticated-orcid":false,"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University  Shihezi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2069-1991","authenticated-orcid":false,"given":"Jinhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy Shihezi University  Shihezi China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,5,25]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201017\u20103070"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u201003048\u2010z"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2021.03.013"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010021\u201001416\u2010w"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2012971"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470\u20102045(21)00494\u20100"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(23)00464\u20106"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2021.119167"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.45"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408\u2010021\u201000425\u20103"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010024\u201006444\u20109"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1600963"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010024\u201001926\u20103"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010023\u201006203\u20102"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c00058"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010021\u201001062\u2010w"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007410\u20103"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010024\u201002245\u20103"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388\u2010023\u201002907\u2010z"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c03756"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.03.003"}],"container-title":["Chemical Biology &amp; 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