{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:11:45Z","timestamp":1786975905935,"version":"build-2736575974"},"reference-count":15,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T00:00:00Z","timestamp":1711065600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB1361"],"award-info":[{"award-number":["SFB1361"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB1292TP21N"],"award-info":[{"award-number":["SFB1292TP21N"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KR2291"],"award-info":[{"award-number":["KR2291"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SI868\/22\u20101"],"award-info":[{"award-number":["SI868\/22\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100021828","name":"German Academic Exchange Service","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100021828","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:p>\n                    Mammalian cells replicate ~\u20093\u2009\u00d7\u200910\n                    <jats:sup>9<\/jats:sup>\n                    base pairs per cell cycle. One of the key molecules that slows down the cell cycle and prevents excessive DNA damage upon DNA replication stress is the checkpoint kinase ataxia\u2010telangiectasia\u2010and\u2010RAD3\u2010related (ATR). Proteolysis\u2010targeting\u2010chimeras (PROTACs) are an innovative pharmacological invention to molecularly dissect, biologically understand, and therapeutically assess catalytic and non\u2010catalytic functions of enzymes. This work defines the first\u2010in\u2010class ATR PROTAC, Abd110\/Ramotac\u20101. It is derived from the ATR inhibitor VE\u2010821 and recruits the E3 ubiquitin\u2010ligase component cereblon to ATR. Abd110 eliminates ATR rapidly in human leukemic cells. This mechanism provokes DNA replication catastrophe and augments anti\u2010leukemic effects of the clinically used ribonucleotide reductase\u20102 inhibitor hydroxyurea. Moreover, Abd110 is more effective than VE\u2010821 against human primary leukemic cells but spares normal primary immune cells. CRISPR\u2010Cas9 screens show that ATR is a dependency factor in 116 myeloid and lymphoid leukemia cells. Treatment of wild\u2010type but not of cereblon knockout cells with Abd110 stalls their proliferation which verifies that ATR elimination is the primary mechanism of Abd110. Altogether, our findings demonstrate specific anti\u2010leukemic effects of an ATR PROTAC.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13638","type":"journal-article","created":{"date-parts":[[2024,3,23]],"date-time":"2024-03-23T01:58:46Z","timestamp":1711159126000},"page":"1958-1965","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Pharmacological degradation of\n                    <scp>ATR<\/scp>\n                    induces antiproliferative\n                    <scp>DNA<\/scp>\n                    replication stress in leukemic cells"],"prefix":"10.1002","volume":"18","author":[{"given":"Anita G.","family":"Kansy","sequence":"first","affiliation":[{"name":"Institute of Toxicology University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramy","family":"Ashry","sequence":"additional","affiliation":[{"name":"Institute of Toxicology University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"},{"name":"Department of Oral Pathology, Faculty of Dentistry Mansoura University  Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Al\u2010Hassan M.","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Institute of Toxicology University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"},{"name":"Department of Zoology, Faculty of Science Aswan University  Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdallah M.","family":"Alfayomy","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Institute of Pharmacy Martin\u2010Luther\u2010University of Halle\u2010Wittenberg  Halle (Saale) Germany"},{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Al\u2010Azhar University  Assiut Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus P.","family":"Radsak","sequence":"additional","affiliation":[{"name":"3<sup>rd<\/sup> Department Medicine University Medical Center Mainz  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanira","family":"Zeyn","sequence":"additional","affiliation":[{"name":"Department of Dermatology University Medical Center Mainz  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Bros","sequence":"additional","affiliation":[{"name":"Department of Dermatology University Medical Center Mainz  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-9261","authenticated-orcid":false,"given":"Wolfgang","family":"Sippl","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Institute of Pharmacy Martin\u2010Luther\u2010University of Halle\u2010Wittenberg  Halle (Saale) Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3973-045X","authenticated-orcid":false,"given":"Oliver H.","family":"Kr\u00e4mer","sequence":"additional","affiliation":[{"name":"Institute of Toxicology University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-020-0376-x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00558-5"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1166"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241310488"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0034-3"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/pharmrev.122.000612"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00736-3"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2018.11.006"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03096-0"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2021.10.011"},{"issue":"7","key":"e_1_2_10_12_1","first-page":"S2090\u20101232","article-title":"Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells","volume":"17","author":"Fischer MA","year":"2023","journal-title":"J Adv Res"},{"issue":"3","key":"e_1_2_10_13_1","first-page":"267","article-title":"Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the Ataxia telangiectasia and RAD3\u2010related (ATR) kinase","volume":"5","author":"Alfayomy AM","year":"2024","journal-title":"Eur J Med Chem"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557-023-01379-8"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.05.001"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.13.9390"}],"container-title":["Molecular 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