RESUMEN
A phenotypic screening of thienodiazepines derived from a hit compound found through a binding assay targeting co-stimulatory molecules on T cells and antigen presenting cells successfully led to the discovery of a thienotriazolodiazepine compound (7f) possessing potent immunosuppressive activity. A chemical biology approach has succeeded in revealing that 7f is a first inhibitor of epigenetic bromodomain-containing proteins. 7f is expected to become an anti-cancer agent as well as an immunosuppressive agent.
Asunto(s)
Antineoplásicos/farmacología , Azepinas/farmacología , Antígenos CD28/metabolismo , Descubrimiento de Drogas , Inmunosupresores/farmacología , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Azepinas/síntesis química , Azepinas/química , Antígenos CD28/inmunología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Histona Acetiltransferasas , Chaperonas de Histonas , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/química , Estructura Molecular , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Fenotipo , Relación Estructura-Actividad , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
A new class of Aurora A kinase inhibitor was created by transforming 4-(5-methyl-3-pyrazoloamino)pyrimidine moiety of VX-680 to 3-cyano-6-(5-methyl-3pyrazoloamino)pyridine. Compound 6 exhibited a potent Aurora A kinase inhibitory activity, excellent selectivity to Aurora B kinase and other 60 kinases, good cell permeability and good PK profile. Therefore compound 6 was effective in antitumor mice model at a dose of 30 mg/kg po qd without decrease of body weight.