3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib

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dc.catalogadorvdr
dc.contributor.authorCabezas, David
dc.contributor.authorDelgado Aguilar, Thalía
dc.contributor.authorSepúlveda Sánchez, Guisselle Alexandra
dc.contributor.authorKrňávková, Petra
dc.contributor.authorVojáčková, Veronika
dc.contributor.authorKryštof, Vladimír
dc.contributor.authorStrnad, Miroslav
dc.contributor.authorNicolás Ignacio, Silva Reyes
dc.contributor.authorEcheverría, Javier
dc.contributor.authorEspinosa Bustos, Christian Marcelo
dc.contributor.authorMellado, Guido
dc.contributor.authorLuo, Jiao
dc.contributor.authorMella, Jaime
dc.contributor.authorSalas Sánchez, Cristian Osvaldo
dc.date.accessioned2025-06-27T17:04:30Z
dc.date.available2025-06-27T17:04:30Z
dc.date.issued2025
dc.description.abstractBcr-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. Methods: 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. Results: Seven purines were easily synthesized (7a–g). Compounds 7a and 7c demonstrated the highest inhibition activity on Bcr-Abl (IC50 = 0.13 and 0.19 μM), surpassing the potency of imatinib (IC50 = 0.33 μM). 7c exhibited the highest potency, with GI50 = 0.30 μM on K562 cells and 1.54 μM on KCL22 cells. The GI50 values obtained for non-neoplastic HEK293T cells indicated that 7c was less toxic than imatinib. Interestingly, KCL22-B8 cells (expressing Bcr-AblT315I) showed greater sensitivity to 7e and 7f than to imatinib (GI50 = 13.80 and 15.43 vs. >20 μM, respectively). In silico analyses, including docking and molecular dynamics studies of Bcr-AblT315I, were conducted to elucidate the enhanced potency of 7e and 7f. Thus, this study provides in silico models to identify novel inhibitors that target a kinase of significance in CML.
dc.fechaingreso.objetodigital2025-06-27
dc.fuente.origenORCID
dc.identifier.doi10.3390/ph18060925
dc.identifier.urihttps://doi.org/10.3390/ph18060925
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/104789
dc.information.autorucEscuela de Química; Delgado Aguilar, Thalia; 0000-0001-8189-0022; 1092170
dc.information.autorucEscuela de Química; Sepúlveda Sánchez, Guisselle Alexandra; S/I; 1088613
dc.information.autorucEscuela de Medicina; Nicolás Ignacio, Silva Reyes; S/I; 178249
dc.information.autorucEscuela de Química; Espinosa Bustos, Christian Marcelo; 0000-0001-6038-8439; 142011
dc.information.autorucEscuela de Química; Salas Sánchez, Cristian Osvaldo; 0000-0001-7620-2459; 101425
dc.issue.numero6
dc.language.isoes
dc.nota.accesoContenido completo
dc.pagina.final27
dc.pagina.inicio1
dc.revistaPharmaceuticals
dc.rights.licenseCC BY 4.0 Attribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject3D-QSAR
dc.subjectChronic myeloid leukaemia
dc.subjectBcr-Abl inhibitors
dc.subjectPurine derivatives
dc.subjectDocking studies
dc.subjectMolecular dynamics
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.title3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib
dc.typeartículo
dc.volumen18
sipa.codpersvinculados1092170
sipa.codpersvinculados1088613
sipa.codpersvinculados178249
sipa.codpersvinculados142011
sipa.codpersvinculados101425
sipa.trazabilidadORCID;2025-06-23
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