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Currently, the clinical treatment of imatinib\u2010resistant patients with tyrosine kinase inhibitors is severely limited by drug resistance and adverse effects. Herein, a dual\u2010targeting proteolysis\u2010targeting chimera (PROTAC) protein drug, termed <jats:sup>PMI<\/jats:sup>Bcr\/Abl\u2010R6, is designed by engrafting an MDM2\/p53 inhibition peptide sequence onto the Bcr\/Abl tetramerization domain. <jats:sup>PMI<\/jats:sup>Bcr\/Abl\u2010R6, harboring a Bcr\/Abl targeting sequence and an MDM2 binding sequence, acts as a PROTAC drug in Ph+ leukemia cells. Its dual\u2010targeting constitution suggests that <jats:sup>PMI<\/jats:sup>Bcr\/Abl\u2010R6 designs to target the tetramerization domain instead of the Abl kinase domain, therefore has the potential to overcome drug resistance mutations in the kinase domain. The efficient ability of <jats:sup>PMI<\/jats:sup>Bcr\/Abl\u2010R6 is demonstrated to simultaneously induce Bcr\/Abl degradation and activate the p53 pathway. <jats:sup>PMI<\/jats:sup>Bcr\/Abl\u2010R6 has the potential to overcome drug resistance in Ph+ leukemias by multiple mechanisms.<\/jats:p>","DOI":"10.1002\/advs.202104850","type":"journal-article","created":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T13:34:52Z","timestamp":1646314492000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Kill Two Birds with One Stone: A Multifunctional Dual\u2010Targeting Protein Drug to Overcome Imatinib Resistance in Philadelphia Chromosome\u2010Positive Leukemia"],"prefix":"10.1002","volume":"9","author":[{"given":"Bohan","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Urology The First Affiliated Hospital Xi'an Jiaotong University  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Endocrinology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jincheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengcheng","family":"He","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4621-9337","authenticated-orcid":false,"given":"Fan","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an 710061 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198810133191506"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-07-077958"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3109\/10428190009148847"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.13.12.7587"},{"key":"e_1_2_8_5_1","first-page":"4236","volume":"62","author":"Nagar B.","year":"2002","journal-title":"Cancer Res."},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra013339"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/00062752-200401000-00006"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00939"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.13801"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-01111-2"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2135"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1747-0285.2010.01054.x"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25102"},{"key":"e_1_2_8_14_1","first-page":"117","volume":"9","author":"Zhao X.","year":"2002","journal-title":"Nat. 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