RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Azepinas/farmacologia , Antígenos CD28/metabolismo , Descoberta de Drogas , Imunossupressores/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Azepinas/síntese química , Azepinas/química , Antígenos CD28/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Histona Acetiltransferases , Chaperonas de Histonas , Humanos , Imunossupressores/síntese química , Imunossupressores/química , Estrutura Molecular , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Fenótipo , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
The next higher homologue of hexamethylenetetramine was synthesized as the proton cryptate H+ @1â Br- (shown schematically), and its X-ray structure determined. The proton trapped by the lone pairs accumulated at the center of the T-symmetric tetraaza cage could not be exchanged or removed, even after heating for three days in 3 M NaOD.
