3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib
<b>Background/Objectives:</b> Bcr-Abl inhibitors such as imatinib have been used to treat chronic myeloid leukemia (CML). However, the efficacy of these drugs has diminished due to mutations in the kinase domain, notably the T315I mutation. Therefore, in this study, new purine derivative...
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2025-06-01
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| author | David Cabezas Thalía Delgado Guisselle Sepúlveda Petra Krňávková Veronika Vojáčková Vladimír Kryštof Miroslav Strnad Nicolás Ignacio Silva Javier Echeverría Christian Espinosa-Bustos Guido Mellado Jiao Luo Jaime Mella Cristian O. Salas |
| author_facet | David Cabezas Thalía Delgado Guisselle Sepúlveda Petra Krňávková Veronika Vojáčková Vladimír Kryštof Miroslav Strnad Nicolás Ignacio Silva Javier Echeverría Christian Espinosa-Bustos Guido Mellado Jiao Luo Jaime Mella Cristian O. Salas |
| author_sort | David Cabezas |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Bcr-Abl inhibitors such as imatinib have been used to treat chronic myeloid leukemia (CML). However, the efficacy of these drugs has diminished due to mutations in the kinase domain, notably the T315I mutation. Therefore, in this study, new purine derivatives were designed as Bcr-Abl inhibitors based on 3D-QSAR studies. <b>Methods:</b> A database of 58 purines that inhibit Bcr-Abl was used to construct 3D-QSAR models. Using chemical information from these models, a small group of new purines was designed, synthesized, and evaluated in Bcr-Abl. Viability assays were conducted on imatinib-sensitive CML cells (K562 and KCL22) and imatinib-resistant cells (KCL22-B8). In silico analyses were performed to confirm the results. <b>Results:</b> Seven purines were easily synthesized (<b>7a</b>–<b>g</b>). Compounds <b>7a</b> and <b>7c</b> demonstrated the highest inhibition activity on Bcr-Abl (IC<sub>50</sub> = 0.13 and 0.19 μM), surpassing the potency of imatinib (IC<sub>50</sub> = 0.33 μM). <b>7c</b> exhibited the highest potency, with GI<sub>50</sub> = 0.30 μM on K562 cells and 1.54 μM on KCL22 cells. The GI<sub>50</sub> values obtained for non-neoplastic HEK293T cells indicated that <b>7c</b> was less toxic than imatinib. Interestingly, KCL22-B8 cells (expressing Bcr-Abl<sup>T315I</sup>) showed greater sensitivity to <b>7e</b> and <b>7f</b> than to imatinib (GI<sub>50</sub> = 13.80 and 15.43 vs. >20 μM, respectively). In silico analyses, including docking and molecular dynamics studies of Bcr-Abl<sup>T315I</sup>, were conducted to elucidate the enhanced potency of <b>7e</b> and <b>7f</b>. Thus, this study provides in silico models to identify novel inhibitors that target a kinase of significance in CML. |
| format | Article |
| id | doaj-art-de18d5fb055d475fa4a78fb2f66fb54a |
| institution | DOAJ |
| issn | 1424-8247 |
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| publishDate | 2025-06-01 |
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| spelling | doaj-art-de18d5fb055d475fa4a78fb2f66fb54a2025-08-20T03:16:35ZengMDPI AGPharmaceuticals1424-82472025-06-0118692510.3390/ph180609253D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to ImatinibDavid Cabezas0Thalía Delgado1Guisselle Sepúlveda2Petra Krňávková3Veronika Vojáčková4Vladimír Kryštof5Miroslav Strnad6Nicolás Ignacio Silva7Javier Echeverría8Christian Espinosa-Bustos9Guido Mellado10Jiao Luo11Jaime Mella12Cristian O. Salas13Instituto de Química, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, ChileDepartamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 7820436, ChileDepartamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 7820436, ChileDepartment of Experimental Biology, Palacký University, Slechtitelu 27, 77900 Olomouc, Czech RepublicDepartment of Experimental Biology, Palacký University, Slechtitelu 27, 77900 Olomouc, Czech RepublicDepartment of Experimental Biology, Palacký University, Slechtitelu 27, 77900 Olomouc, Czech RepublicLaboratory of Growth Regulators, Palacký University and Institute of Experimental Botany, The Czech Academy of Sciences, Slechtitelu 27, 77900 Olomouc, Czech RepublicDepartamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 7820436, ChileDepartamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago de Chile 9170022, ChileDepartamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 7820436, ChileDepartamento de Ingeniería Informática, Facultad de Ingeniería, Universidad Católica de Temuco, Temuco 4780000, ChileInstituto de Química, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, ChileInstituto de Química, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, ChileDepartamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 7820436, Chile<b>Background/Objectives:</b> Bcr-Abl inhibitors such as imatinib have been used to treat chronic myeloid leukemia (CML). However, the efficacy of these drugs has diminished due to mutations in the kinase domain, notably the T315I mutation. Therefore, in this study, new purine derivatives were designed as Bcr-Abl inhibitors based on 3D-QSAR studies. <b>Methods:</b> A database of 58 purines that inhibit Bcr-Abl was used to construct 3D-QSAR models. Using chemical information from these models, a small group of new purines was designed, synthesized, and evaluated in Bcr-Abl. Viability assays were conducted on imatinib-sensitive CML cells (K562 and KCL22) and imatinib-resistant cells (KCL22-B8). In silico analyses were performed to confirm the results. <b>Results:</b> Seven purines were easily synthesized (<b>7a</b>–<b>g</b>). Compounds <b>7a</b> and <b>7c</b> demonstrated the highest inhibition activity on Bcr-Abl (IC<sub>50</sub> = 0.13 and 0.19 μM), surpassing the potency of imatinib (IC<sub>50</sub> = 0.33 μM). <b>7c</b> exhibited the highest potency, with GI<sub>50</sub> = 0.30 μM on K562 cells and 1.54 μM on KCL22 cells. The GI<sub>50</sub> values obtained for non-neoplastic HEK293T cells indicated that <b>7c</b> was less toxic than imatinib. Interestingly, KCL22-B8 cells (expressing Bcr-Abl<sup>T315I</sup>) showed greater sensitivity to <b>7e</b> and <b>7f</b> than to imatinib (GI<sub>50</sub> = 13.80 and 15.43 vs. >20 μM, respectively). In silico analyses, including docking and molecular dynamics studies of Bcr-Abl<sup>T315I</sup>, were conducted to elucidate the enhanced potency of <b>7e</b> and <b>7f</b>. Thus, this study provides in silico models to identify novel inhibitors that target a kinase of significance in CML.https://www.mdpi.com/1424-8247/18/6/9253D-QSARchronic myeloid leukaemiaBcr-Abl inhibitorspurine derivativesdocking studiesmolecular dynamics |
| spellingShingle | David Cabezas Thalía Delgado Guisselle Sepúlveda Petra Krňávková Veronika Vojáčková Vladimír Kryštof Miroslav Strnad Nicolás Ignacio Silva Javier Echeverría Christian Espinosa-Bustos Guido Mellado Jiao Luo Jaime Mella Cristian O. Salas 3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib Pharmaceuticals 3D-QSAR chronic myeloid leukaemia Bcr-Abl inhibitors purine derivatives docking studies molecular dynamics |
| title | 3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib |
| title_full | 3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib |
| title_fullStr | 3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib |
| title_full_unstemmed | 3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib |
| title_short | 3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib |
| title_sort | 3d qsar design of new bcr abl inhibitors based on purine scaffold and cytotoxicity studies on cml cell lines sensitive and resistant to imatinib |
| topic | 3D-QSAR chronic myeloid leukaemia Bcr-Abl inhibitors purine derivatives docking studies molecular dynamics |
| url | https://www.mdpi.com/1424-8247/18/6/925 |
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