Bcr-Abl and Btk kinases are among the targets that have been considered for the treatment of leukemia. Therefore, several strategies have focused on the use of inhibitors as chemotherapeutic tools to treat these types of leukemia, such as imatinib (for Bcr-Abl) or ibrutinib (for Btk). However, the efficacy of these drugs has been reduced due to resistance mechanisms, which have motivated the development of new and more effective compounds. In this study, we designed, synthesized and evaluated 2,6,9-trisubstituted purine derivatives as novel Bcr-Abl and Btk inhibitors. We identified 5c and 5d as potent inhibitors of both kinases (IC50 values of 40 nM and 0.58/0.66 μM for Abl and Btk, respectively). From docking and QSAR analyses, we concluded that fluorination of the arylpiperazine system is detrimental to the activity against two kinases, and we also validated our hypothesis that the substitution on the 6-phenylamino ring is important for the inhibition of both kinases. In addition, our studies indicated that most compounds could suppress the proliferation of leukemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos cells) at low micromolar concentrations in vitro. Finally, we preliminarily demonstrated that 5c inhibited the downstream signaling of both kinases in the respective cell models. Therefore, 5c or 5d possessed potency to be further optimized as anti-leukemia drugs by simultaneously inhibiting the Bcr-Abl and Btk kinases.

Departamento de Farmacia Facultad de Química y de Farmacia Pontificia Universidad Católica de Chile 702843 Santiago de Chile Chile

Departamento de Química Orgánica Facultad de Química y de Farmacia Pontificia Universidad Católica de Chile 702843 Santiago de Chile Chile

Instituto de Química y Bioquímica Facultad de Ciencias Universidad de Valparaíso 2360102 Av Gran Bretaña 1111 Playa Ancha Valparaíso Casilla 5030 Chile

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

Laboratory of Growth Regulators Palacký University and Institute of Experimental Botany The Czech Academy of Sciences Slechtitelu 27 783 71 Olomouc Czech Republic

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