RESUMEN
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) containing the T315I mutation.
Asunto(s)
Piperazinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Aurora Quinasas , Línea Celular Tumoral , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/metabolismo , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antimaláricos/uso terapéutico , Antiparkinsonianos/uso terapéutico , Trastornos Parkinsonianos/tratamiento farmacológico , Pirimidinas/uso terapéutico , Antimaláricos/síntesis química , Antiparkinsonianos/síntesis química , Humanos , Modelos Químicos , Pirimidinas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumors, and lead to aneuploidy and tumorigenesis. Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. This compound causes profound inhibition of tumor growth in a variety of in vivo xenograft models, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses. Our data indicate that Aurora kinase inhibition provides a new approach for the treatment of multiple human malignancies.
Asunto(s)
Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Piperazinas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Apoptosis/fisiología , Aurora Quinasas , Ciclo Celular/fisiología , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Femenino , Histonas/metabolismo , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Piperazinas/química , Piperazinas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , RatasRESUMEN
Water soluble prodrugs of hybrid free radical scavenger/iron chelating molecules, based on 3,5-disubstituted-4-hydroxyphenyl derivatives and 3-hydroxy-2-methyl-4(1H)-pyridinone (deferiprone), have been prepared. Related hybrid molecules containing a covalent poly(ethylene)glycol or an amine linker were also synthesized.