RESUMEN
A series of 4-((pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)phenyl-3-benzamide derivatives and 4-((imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-)phenyl-3-benzamide derivatives were designed, synthesized as new BCR-ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. These new compounds were screened for BCR-ABL1 kinase inhibitory activity, and most of them appeared good inhibitory activity against BCR-ABL1 kinase. One of the most potent compounds 16a strongly suppressed BCR-ABL1 kinase with IC50 value of 8.5nM. The tested compounds 16a and 16i showed strong inhibitory activities against K562 with IC50 value of less than 2nM. Molecular docking studies indicated that these compounds fitted well with the active site of BCR-ABL1 protein. The results showed these inhibitors may serve as lead compounds for further developing new drugs targeted BCR-ABL kinase.
Asunto(s)
Benzamidas/química , Diseño de Fármacos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Benzamidas/metabolismo , Benzamidas/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Concentración 50 Inhibidora , Células K562 , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Relación Estructura-ActividadRESUMEN
A series of novel morpholin-3-one-fused quinazoline derivatives were designed, synthesized and evaluated as EGFR tyrosine kinase inhibitors. Nineteen compounds showed significant inhibitory activities against EGFR(wt) kinase (IC50<1 µM). Compound a8 demonstrated the most potent inhibitory activity toward EGFR(wt) (IC50=53.1 nM). Compound a7 and a8 showed excellent inhibitory activities against mutant EGFR(T790M/L858R) and strong antiproliferative activity against H358 and A549 cell lines. Finally, molecular docking studies were performed to predict the possible binding mode of the target compounds. It is believed that this work would be very useful for designing a new series of tyrosine kinase inhibitors targeting EGFR.
Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Morfolinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Morfolinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
4-(Pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives have been proposed as new BCR-ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. In the present study, a series of 4-(pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives were synthesized and their activities against BCR-ABL1 kinase in vitro were evaluated by using Kinase-Glo assay. All new compounds showed from moderate to potent activities against wild-type (wt) BCR-ABL1 kinase with an IC50 range from 14.2 to 326.0nM. Among them, seven compounds exhibited BCR-ABL1 kinase inhibitory activities with IC50 values less than 50nM. Compound 7a displayed the most potent inhibitory activity to BCR-ABL kinase (IC50: 14.2nM). Docking simulation was performed for compounds 7a and 7i into the BCR-ABL kinase structure active site to determine the probable binding model. The preliminary structure-activity relationship was discussed. The interesting activities of these compounds may make them promising candidates as therapeutic agents for chronic myelogenous leukemia.