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
Thalia Delgado,
Denisa Veselá,
Hana Dostálová,
Vladimír Kryštof,
Veronika Vojáčková,
Radek Jorda,
Alejandro Castro,
Jeanluc Bertrand,
Gildardo Rivera,
Mario Faúndez,
Miroslav Strnad,
Christian Espinosa-Bustos,
Cristian O. Salas
Affiliations
Thalia Delgado
Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile
Denisa Veselá
Department of Experimental Biology, Palacký University Olomouc, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
Hana Dostálová
Department of Experimental Biology, Palacký University Olomouc, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
Vladimír Kryštof
Department of Experimental Biology, Palacký University Olomouc, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
Veronika Vojáčková
Department of Experimental Biology, Palacký University Olomouc, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
Radek Jorda
Department of Experimental Biology, Palacký University Olomouc, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
Alejandro Castro
Laboratorio de Bioproductos Farmacéuticos y Cosméticos, Centro de Excelencia en Medicina Traslacional, Facultad de Medicina, Universidad de La Frontera, Av. Francisco Salazar 01145, Temuco 4780000, Chile
Jeanluc Bertrand
Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile
Gildardo Rivera
Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Boulevard del Maestro s/n, Reynosa 88710, Mexico
Mario Faúndez
Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile
Miroslav Strnad
Laboratory of Growth Regulators, Institute of Experimental Botany of the Czech Academy of Sciences & Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic
Christian Espinosa-Bustos
Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile
Cristian O. Salas
Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago de Chile 702843, Chile
Bcr-Abl is an oncoprotein with aberrant tyrosine kinase activity involved in the progression of chronic myeloid leukemia (CML) and has been targeted by inhibitors such as imatinib and nilotinib. 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 μM) than imatinib and nilotinib and exerted the most potent antiproliferative properties on three CML cells harboring the Bcr-Abl rearrangement (GI50 = 0.7–1.3 μM). 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 > 20 μM) compared to 11b–f (GI50 = 6.4–11.5 μM). Molecular docking studies explained the structure–activity 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.