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ATR inhibitors have in recent times demonstrated promising clinical potential, and are currently being evaluated in the clinic. However, despite the considerable optimism for clinical success of these inhibitors, reports of associated normal tissues toxicities remain a concern and can compromise their utility. Here, ICT10336 is reported, a newly developed hypoxia\u2010responsive prodrug of ATR inhibitor, AZD6738, which is hypoxia\u2010activated and specifically releases AZD6738 only in hypoxic conditions, in vitro. This hypoxia\u2010selective release of AZD6738 inhibited ATR activation (T1989 and S428 phosphorylation) and subsequently abrogated HIF1a\u2010mediated adaptation of hypoxic cancers cells, thus selectively inducing cell death in 2D and 3D cancer models. Importantly, in normal tissues, ICT10336 is demonstrated to be metabolically stable and less toxic to normal cells than its active parent agent, AZD6738. In addition, ICT10336 exhibited a superior and efficient multicellular penetration ability in 3D tumor models, and selectively eradicated cells at the hypoxic core compared to AZD6738. In summary, the preclinical data demonstrate a new strategy of tumor\u2010targeted delivery of ATR inhibitors with significant potential of enhancing the therapeutic index.<\/jats:p>","DOI":"10.1002\/advs.202403831","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T13:29:31Z","timestamp":1720445371000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Hypoxia\u2010Responsive Prodrug of ATR Inhibitor, AZD6738, Selectively Eradicates Treatment\u2010Resistant Cancer Cells"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6110-2746","authenticated-orcid":false,"given":"Francis M.","family":"Barnieh","sequence":"first","affiliation":[{"name":"Institute of Cancer Therapeutics Faculty of Life Sciences University of Bradford  Richmond Road Bradford BD7 1DP United\u00a0Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goreti Ribeiro","family":"Morais","sequence":"additional","affiliation":[{"name":"Institute of Cancer Therapeutics Faculty of Life Sciences University of Bradford  Richmond Road Bradford BD7 1DP United\u00a0Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Loadman","sequence":"additional","affiliation":[{"name":"Institute of Cancer Therapeutics Faculty of Life Sciences University of Bradford  Richmond Road Bradford BD7 1DP United\u00a0Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Falconer","sequence":"additional","affiliation":[{"name":"Institute of Cancer Therapeutics Faculty of Life Sciences University of Bradford  Richmond Road Bradford BD7 1DP United\u00a0Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherif F.","family":"El\u2010Khamisy","sequence":"additional","affiliation":[{"name":"Institute of Cancer Therapeutics Faculty of Life Sciences University of Bradford  Richmond Road Bradford BD7 1DP United\u00a0Kingdom"},{"name":"School of Biosciences, the Healthy Lifespan Institute and the Institute of Neuroscience University of Sheffield  Sheffield S10 2TN United\u00a0Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,8]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2022.836417"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-016-5319-8"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12092392"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1001389"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2021.188521"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08467"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.573"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11412"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2009.07.001"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.703802"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.742139"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01151-6"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-18-0470"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2018.03.003"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-2997"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2010.09.005"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2076"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2189"},{"key":"e_1_2_10_19_1","first-page":"4902","volume":"15","author":"Haciefendi A.","year":"2023","journal-title":"Am. 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