RESUMEN
2,7-Diamino-thiazolo[4,5-d]pyrimidine analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these thiazolopyrimidine compounds are reported.
Asunto(s)
Antineoplásicos/síntesis química , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/análogos & derivados , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacologíaRESUMEN
A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine was synthesized and found to have potent dual EGFR/HER2 kinase inhibitory activity. The structure-based drug design of this molecule as well as the kinase and cellular inhibition of HER2 kinase dependent cell lines will be discussed.
Asunto(s)
Diaminas/farmacología , Receptores ErbB/metabolismo , Oxadiazoles/farmacología , Pirimidinas/farmacología , Receptor ErbB-2/metabolismo , Línea Celular , Diaminas/síntesis química , Diaminas/metabolismo , Diseño de Fármacos , Receptores ErbB/antagonistas & inhibidores , Células HeLa , Humanos , Oxadiazoles/síntesis química , Oxadiazoles/metabolismo , Unión Proteica , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Modulation of aberrant cell cycle regulation is a potential therapeutic strategy applicable to a wide range of tumor types. JNJ-7706621 is a novel cell cycle inhibitor that showed potent inhibition of several cyclin-dependent kinases (CDK) and Aurora kinases and selectively blocked proliferation of tumor cells of various origins but was about 10-fold less effective at inhibiting normal human cell growth in vitro. In human cancer cells, treatment with JNJ-7706621 inhibited cell growth independent of p53, retinoblastoma, or P-glycoprotein status; activated apoptosis; and reduced colony formation. At low concentrations, JNJ-7706621 slowed the growth of cells and at higher concentrations induced cytotoxicity. Inhibition of CDK1 kinase activity, altered CDK1 phosphorylation status, and interference with downstream substrates such as retinoblastoma were also shown in human tumor cells following drug treatment. Flow cytometric analysis of DNA content showed that JNJ-7706621 delayed progression through G1 and arrested the cell cycle at the G2-M phase. Additional cellular effects due to inhibition of Aurora kinases included endoreduplication and inhibition of histone H3 phosphorylation. In a human tumor xenograft model, several intermittent dosing schedules were identified that produced significant antitumor activity. There was a direct correlation between total cumulative dose given and antitumor effect regardless of the dosing schedule. These results show the therapeutic potential of this novel cell cycle inhibitor and support clinical evaluation of JNJ-7706621.
Asunto(s)
Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Triazoles/farmacología , Animales , Aurora Quinasas , Línea Celular Tumoral , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Femenino , Células HeLa , Humanos , Melanoma/tratamiento farmacológico , Melanoma/enzimología , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of 1-acyl-1H-[1,2,4]triazole-3,5-diamine analogues were synthesized as cyclin-dependent kinase (CDK) inhibitors. These compounds showed potent and selective CDK1 and CDK2 inhibitory activities and inhibited in vitro cellular proliferation in various human tumor cells. Representative compound 3b demonstrated in vivo efficacy in a human melanoma A375 xenograft model in nude mice.
Asunto(s)
Antineoplásicos/síntesis química , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Diaminas/síntesis química , Inhibidores Enzimáticos/síntesis química , Triazoles/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Diaminas/farmacocinética , Diaminas/farmacología , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Ratones , Ratones Desnudos , Estructura Molecular , Ratas , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
A novel series of 4-aryl-5-cyano-2-aminopyrimidines were synthesized and found to have potent VEGF-R2 kinase inhibitory activity. Structure-activity relationships were investigated and compound 14a was shown to be efficacious in a mouse model of corneal neovascularization.
Asunto(s)
Neovascularización de la Córnea/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Pirimidinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Neovascularización de la Córnea/patología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Ratones , Pirimidinas/síntesis química , Relación Estructura-ActividadRESUMEN
A novel series of 2,6-diamino-3-acylpyridines were designed and synthesized as cyclin-dependent kinase (CDK) inhibitors. The representative compounds 2r and 11 showed potent CDK1 and CDK2 inhibitory activities and inhibited cellular proliferation in HeLa, HCT116, and A375 tumor cells.