{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T14:54:35Z","timestamp":1779375275796,"version":"3.53.1"},"reference-count":43,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T00:00:00Z","timestamp":1746489600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA243529"],"award-info":[{"award-number":["R01CA243529"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2025,5,27]]},"abstract":"<jats:p>Mithramycin (MTM) is a polyketide anticancer natural product, which functions by noncovalent binding to DNA in the minor groove without intercalation, resulting in inhibiting transcription at G\/C\u2010rich promoters. MTM is a potent inhibitor of cancer cells, such as Ewing sarcoma, driven by abnormal fusions involving E26 transformation\u2010specific (ETS) family transcription factors friend leukemia integration 1 (FLI1) and ETS\u2010related gene (ERG). However, MTM is rather toxic and nonselective; therefore, safer, selective analogues of MTM are required for use in the clinic as anticancer drugs. Herein, by using a combination of X\u2010ray crystallographic, biophysical, and cell and molecular biological techniques, the structural and functional consequences of 3\u2010side chain methylation at positions 5, 6, and 7 of the indole ring of the potent analogue MTM SA\u2010Trp are explored. The conformation of the analogues in complexes with DNA, their DNA binding function, cytotoxicity, selectivity, and potency as transcription antagonists depended on the position of the methylation. MTM SA\u20105\u2010methyl\u2010Trp emerged as the most selective analogue, presumably due to the right balance of the DNA binding and the solvent exposure of the 3\u2010side chain. This study demonstrates that minor chemical changes can have strong effects in analogue development and paves the way to further development of next\u2010generation MTM analogues.<\/jats:p>","DOI":"10.1002\/cbic.202401084","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T22:07:02Z","timestamp":1744927622000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Position of Indole Methylation Controls the Structure, DNA Binding, and Cellular Functions of Mithramycin SA\u2010Trp Analogues"],"prefix":"10.1002","volume":"26","author":[{"given":"Caixia","family":"Hou","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy University of Kentucky  Lexington KY 40536 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhas","family":"Bhosale","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical 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