{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T06:11:26Z","timestamp":1760854286620,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T00:00:00Z","timestamp":1658880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Center of Poland","award":["2014\/15\/B\/NZ7\/00966"],"award-info":[{"award-number":["2014\/15\/B\/NZ7\/00966"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The search is ongoing for new anticancer therapeutics that would overcome resistance to chemotherapy. This includes chronic myeloid leukemia, particularly suitable for the studies of novel anticancer compounds due to its homogenous and well-known genetic background. Here we show anticancer efficacy of novel dicarboximide denoted BK124.1 (C31H37ClN2O4) in a mouse CML xenograft model and in vitro in two types of chemoresistant CML cells: MDR1 blasts and in CD34+ patients\u2019 stem cells (N = 8) using immunoblotting and flow cytometry. Intraperitoneal administration of BK124.1 showed anti-CML efficacy in the xenograft mouse model (N = 6) comparable to the commonly used imatinib and hydroxyurea. In K562 blasts, BK124.1 decreased the protein levels of BCR-ABL1 kinase and its downstream effectors, resulting in G2\/M cell cycle arrest and apoptosis associated with FOXO3a\/p21waf1\/cip1 upregulation in the nucleus. Additionally, BK124.1 evoked massive apoptosis in multidrug resistant K562-MDR1 cells (IC50 = 2.16 \u03bcM), in CD34+ cells from CML patients (IC50 = 1.5 \u00b5M), and in the CD34+\/CD38\u2212 subpopulation consisting of rare, drug-resistant cancer initiating stem cells. Given the advantages of BK124.1 as a potential chemotherapeutic and its unique ability to overcome BCR-ABL1 dependent and independent multidrug resistance mechanisms, future development of BK124.1 could offer a cure for CML and other cancers resistant to present drugs.<\/jats:p>","DOI":"10.3390\/cancers14153641","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T04:59:16Z","timestamp":1658897956000},"page":"3641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Dicarboximide BK124.1 Breaks Multidrug Resistance and Shows Anticancer Efficacy in Chronic Myeloid Leukemia Preclinical Models and Patients\u2019 CD34+\/CD38\u2212 Leukemia Stem Cells"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3560-6339","authenticated-orcid":false,"given":"Iga","family":"Stukan","sequence":"first","affiliation":[{"name":"Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marek","family":"Gryzik","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0917-5611","authenticated-orcid":false,"given":"Gra\u017cyna","family":"Hoser","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland"},{"name":"Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7800-873X","authenticated-orcid":false,"given":"Andrew","family":"Want","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wioleta","family":"Grabowska-Pyrzewicz","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikolaj","family":"Zdioruk","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1174-2208","authenticated-orcid":false,"given":"Mariola","family":"Napi\u00f3rkowska","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9628-214X","authenticated-orcid":false,"given":"Marcin","family":"Cie\u015blak","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2979-8867","authenticated-orcid":false,"given":"Karolina","family":"Kr\u00f3lewska-Goli\u0144ska","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4084-4334","authenticated-orcid":false,"given":"Barbara","family":"Nawrot","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3858-8180","authenticated-orcid":false,"given":"Grzegorz","family":"Basak","sequence":"additional","affiliation":[{"name":"Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4525-2004","authenticated-orcid":false,"given":"Urszula","family":"Wojda","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Testing of Higher Standard, Nencki Institute of Experimental Biology of Polish Academy of 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