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However, despite their efficacy in the treatment of CML, a mechanism of resistance to these drugs associated with mutations in the kinase region has emerged. Therefore, in this work, we report the synthesis of 14 new 2,6,9-trisubstituted purines designed from our previous Bcr-Abl inhibitors. Here, we highlight 11b, which showed higher potency against Bcr-Abl (IC50 = 0.015 \u03bcM) than imatinib and nilotinib and exerted the most potent antiproliferative properties on three CML cells harboring the Bcr-Abl rearrangement (GI50 = 0.7\u20131.3 \u03bcM). In addition, these purines were able to inhibit the growth of KCL22 cell lines expressing Bcr-AblT315I, Bcr-AblE255K, and Bcr-AblY253H point mutants in micromolar concentrations. Imatinib and nilotinib were ineffective in inhibiting the growth of KCL22 cells expressing Bcr-AblT315I (GI50 &gt; 20 \u03bcM) compared to 11b\u2013f (GI50 = 6.4\u201311.5 \u03bcM). Molecular docking studies explained the structure\u2013activity relationship of these purines in Bcr-AblWT and Bcr-AblT315I. Finally, cell cycle cytometry assays and immunodetection showed that 11b arrested the cells in G1 phase, and that 11b downregulated the protein levels downstream of Bcr-Abl in these cells.<\/jats:p>","DOI":"10.3390\/pharmaceutics16050649","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T10:26:36Z","timestamp":1715682396000},"page":"649","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["New Inhibitors of Bcr-Abl Based on 2,6,9-Trisubstituted Purine Scaffold Elicit Cytotoxicity in Chronic Myeloid Leukemia-Derived Cell Lines Sensitive and Resistant to TKIs"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8189-0022","authenticated-orcid":false,"given":"Thalia","family":"Delgado","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago de Chile 702843, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denisa","family":"Vesel\u00e1","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Palack\u00fd University Olomouc, \u0160lechtitel\u016f 27, 783 71 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6123-6450","authenticated-orcid":false,"given":"Hana","family":"Dost\u00e1lov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Palack\u00fd University Olomouc, \u0160lechtitel\u016f 27, 783 71 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5838-2118","authenticated-orcid":false,"given":"Vladim\u00edr","family":"Kry\u0161tof","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Palack\u00fd University Olomouc, \u0160lechtitel\u016f 27, 783 71 Olomouc, Czech Republic"},{"name":"Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palack\u00fd University Olomouc, Hn\u011bvot\u00ednsk\u00e1 5, 779 00 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Voj\u00e1\u010dkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Palack\u00fd University Olomouc, \u0160lechtitel\u016f 27, 783 71 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4905-7126","authenticated-orcid":false,"given":"Radek","family":"Jorda","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Palack\u00fd University Olomouc, \u0160lechtitel\u016f 27, 783 71 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8360-8027","authenticated-orcid":false,"given":"Alejandro","family":"Castro","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioproductos Farmac\u00e9uticos y Cosm\u00e9ticos, Centro de Excelencia en Medicina Traslacional, Facultad de Medicina, Universidad de La Frontera, Av. Francisco Salazar 01145, Temuco 4780000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6247-0652","authenticated-orcid":false,"given":"Jeanluc","family":"Bertrand","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago de Chile 702843, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9842-4167","authenticated-orcid":false,"given":"Gildardo","family":"Rivera","sequence":"additional","affiliation":[{"name":"Laboratorio de Biotecnolog\u00eda Farmac\u00e9utica, Centro de Biotecnolog\u00eda Gen\u00f3mica, Instituto Polit\u00e9cnico Nacional, Boulevard del Maestro s\/n, Reynosa 88710, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5507-3579","authenticated-orcid":false,"given":"Mario","family":"Fa\u00fandez","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago de Chile 702843, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miroslav","family":"Strnad","sequence":"additional","affiliation":[{"name":"Laboratory of Growth Regulators, Institute of Experimental Botany of the Czech Academy of Sciences & Palack\u00fd University, \u0160lechtitel\u016f 27, 783 71 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6038-8439","authenticated-orcid":false,"given":"Christian","family":"Espinosa-Bustos","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago de Chile 702843, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7620-2459","authenticated-orcid":false,"given":"Cristian O.","family":"Salas","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago de Chile 702843, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"00665","DOI":"10.3389\/fonc.2019.00665","article-title":"New Approaches and Treatment Combinations for the Management of Chronic Myeloid Leukemia","volume":"9","author":"Westerweel","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.leukres.2010.04.016","article-title":"BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review","volume":"34","author":"An","year":"2010","journal-title":"Leuk. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13057","DOI":"10.1038\/s41598-022-17271-3","article-title":"Detection of kinase domain mutations in BCR::ABL1 leukemia by ultra-deep sequencing of genomic DNA","volume":"12","author":"Dorado","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1158\/1078-0432.CCR-09-3314","article-title":"Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia","volume":"17","author":"Deininger","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s13045-018-0624-2","article-title":"Past, present, and future of Bcr-Abl inhibitors: From chemical development to clinical efficacy","volume":"11","author":"Rossari","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"106552","DOI":"10.1016\/j.phrs.2022.106552","article-title":"Properties of FDA-approved small molecule protein kinase inhibitors: A 2023 update","volume":"187","author":"Roskoski","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/nrc1567","article-title":"Mechanisms of BCR\u2013ABL in the pathogenesis of chronic myelogenous leukaemia","volume":"5","author":"Ren","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Alves, R., Gon\u00e7alves, A.C., Rutella, S., Almeida, A.M., De Las Rivas, J., Trougakos, I.P., and Sarmento Ribeiro, A.B. (2021). Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia\u2014From Molecular Mechanisms to Clinical Relevance. Cancers, 13.","DOI":"10.3390\/cancers13194820"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1111\/cbdd.13801","article-title":"Recent advances in Bcr-Abl tyrosine kinase inhibitors for overriding T315I mutation","volume":"97","author":"Liu","year":"2021","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1517\/13543776.2015.1012155","article-title":"Bcr-Abl tyrosine kinase inhibitors: A patent review","volume":"25","author":"Desogus","year":"2015","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9244","DOI":"10.1073\/pnas.0600001103","article-title":"Activity of dual SRC-ABL inhibitors highlights the role of BCR\/ABL kinase dynamics in drug resistance","volume":"103","author":"Azam","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bertrand, J., Dost\u00e1lov\u00e1, H., Krystof, V., Jorda, R., Castro, A., Mella, J., Espinosa-Bustos, C., Mar\u00eda Zarate, A., and Salas, C.O. (2020). New 2,6,9-trisubstituted purine derivatives as Bcr-Abl and Btk inhibitors and as promising agents against leukemia. Bioorganic Chem., 94.","DOI":"10.1016\/j.bioorg.2019.103361"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bertrand, J., Dost\u00e1lov\u00e1, H., Kry\u0161tof, V., Jorda, R., Delgado, T., Castro-Alvarez, A., Mella, J., Cabezas, D., Fa\u00fandez, M., and Espinosa-Bustos, C. (2022). Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14061294"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra Precision Glide:\u2009 Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein\u2013Ligand Complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"744373","DOI":"10.3389\/fonc.2021.744373","article-title":"Somatic Mutations in Oncogenes Are in Chronic Myeloid Leukemia Acquired De Novo via Deregulated Base-Excision Repair and Alternative Non-Homologous End Joining","volume":"11","author":"Curik","year":"2021","journal-title":"Front Oncol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6808","DOI":"10.3390\/molecules20046808","article-title":"Synthesis and pharmacophore modelling of 2,6,9-trisubstituted purine derivatives and their potential role as apoptosis-inducing agents in cancer cell lines","volume":"20","author":"Tapia","year":"2015","journal-title":"Molecules"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1021\/acs.jctc.7b01170","article-title":"Predicting the Conformational Variability of Abl Tyrosine Kinase using Molecular Dynamics Simulations and Markov State Models","volume":"14","author":"Meng","year":"2018","journal-title":"J. Chem. Theory Comput."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1038\/sj.bjc.6603170","article-title":"AMN107 (nilotinib): A novel and selective inhibitor of BCR-ABL","volume":"94","author":"Weisberg","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1182\/blood-2005-03-1036","article-title":"High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: Correlation with clonal cytogenetic evolution but not response to therapy","volume":"106","author":"Willis","year":"2005","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nature14119","article-title":"Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation","volume":"519","author":"Pemovska","year":"2015","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1021\/tx200211v","article-title":"Improving Drug Candidates by Design: A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and Safety","volume":"24","author":"Meanwell","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1PII of original article: S0169-409X(96)00423-1","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular Properties That Influence the Oral Bioavailability of Drug Candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/5\/649\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:44:18Z","timestamp":1760107458000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/5\/649"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,11]]},"references-count":26,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["pharmaceutics16050649"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16050649","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,11]]}}}