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Several potent ATR inhibitors are currently undergoing various stages of clinical trials, but none have yet received FDA approval due to unclear regulatory mechanisms. In this study, we discovered a potent and selective ATR degrader. Its kinase\u2010independent regulatory functions in acute myeloid leukemia (AML) cells were elucidated using this proteolysis\u2010targeting chimera (PROTAC) molecule as a probe. The ATR degrader, <jats:bold>8\u2009i<\/jats:bold>, exhibited significantly different cellular phenotypes compared to the ATR kinase inhibitor <jats:bold>1<\/jats:bold>. Mechanistic studies revealed that ATR deletion led to breakdown in the nuclear envelope, causing genome instability and extensive DNA damage. This would increase the expression of p53 and triggered immediately p53\u2010mediated apoptosis signaling pathway, which was earlier and more effective than ATR kinase inhibition. Based on these findings, the in vivo anti\u2010proliferative effects of ATR degrader <jats:bold>8\u2009i<\/jats:bold> were assessed using xenograft models. The degrader significantly inhibited the growth of AML\u2005cells in vivo, unlike the ATR inhibitor. These results suggest that the marked anti\u2010AML activity is regulated by the kinase\u2010independent functions of the ATR protein. Consequently, developing potent and selective ATR degraders could be a promising strategy for treating AML.<\/jats:p>","DOI":"10.1002\/anie.202318568","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T05:28:40Z","timestamp":1709530120000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Discovery of Selective and Potent ATR Degrader for Exploration its Kinase\u2010Independent Functions in Acute Myeloid Leukemia Cells"],"prefix":"10.1002","volume":"63","author":[{"given":"Yubo","family":"Wang","sequence":"first","affiliation":[{"name":"The State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University  Tianjin 300071 P. R. 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