Background/Objectives: 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. 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.

Centro de Investigación Desarrollo e Innovación de Productos Bioactivos Escuela de Química y Farmacia Facultad de Farmacia Universidad de Valparaíso Valparaíso 2360102 Chile

Departamento de Ciencias del Ambiente Facultad de Química y Biología Universidad de Santiago de Chile Santiago de Chile 9170022 Chile

Departamento de Farmacia Facultad de Química y de Farmacia Pontificia Universidad Católica de Chile Santiago de Chile 7820436 Chile

Departamento de Ingeniería Informática Facultad de Ingeniería Universidad Católica de Temuco Temuco 4780000 Chile

Departamento de Química Orgánica Facultad de Química y de Farmacia Pontificia Universidad Católica de Chile Santiago de Chile 7820436 Chile

Department of Experimental Biology Palacký University Slechtitelu 27 77900 Olomouc Czech Republic

Instituto de Química Facultad de Ciencias Universidad de Valparaíso Valparaíso 2360102 Chile

Laboratory of Growth Regulators Palacký University and Institute of Experimental Botany The Czech Academy of Sciences Slechtitelu 27 77900 Olomouc Czech Republic

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