RESUMO
Clinical studies have shown that inhibitors of bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, have antitumor activity and efficacy. The BET protein has two domains, BD1 and BD2, and we previously focused on BD1 and reported orally bioavailable BD1-selective inhibitors. In this study, we obtained a BD1 inhibitor, a more potent and highly selective pyrazolopyridone derivative 13a, and confirmed its in vivo efficacy.
Assuntos
Piridonas , Humanos , Administração Oral , Relação Estrutura-Atividade , Animais , Piridonas/química , Piridonas/farmacologia , Piridonas/síntese química , Piridonas/farmacocinética , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Descoberta de Drogas , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Estrutura Molecular , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Camundongos , Domínios Proteicos , Relação Dose-Resposta a Droga , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Ratos , Proteínas que Contêm BromodomínioRESUMO
We explored novel immunosuppressive agents with immune tolerance using a phenotypic drug discovery strategy, focusing on costimulatory molecules in T cells, and obtained triazolothienodiazepine derivatives. Their mechanism of action is to inhibit the bromodomain and extra-terminal domain (BET) family, as we have previously reported. Selective inhibition of the first bromodomain (BD1) of the BET family is expected to exert antitumor and immunosuppressive effects, similar to BET inhibitors. This study identified furopyridine derivatives 7 and 8 with high BD1 inhibitory activity and high selectivity over BD2. Compound 7 was found to be orally bioavailable and exhibited anti-inflammatory activity in a lipopolysaccharide-induced model.
Assuntos
Piridinas , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Animais , Humanos , Administração Oral , Relação Estrutura-Atividade , Camundongos , Descoberta de Drogas , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Estrutura Molecular , Ratos , Domínios ProteicosRESUMO
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
Today ABR ABR: Auditory B ainstem Responses) characteristics are widely and qualitatively used, and they ar e mainly used for clinical application of a consciousness obstacle, brain death and some consciousness level, vegetative state and so on, as the very useful inspection method. Until now, many various characteristics and models about these brain waves have been reported. But the theor ies and experiments of ABR are still more needed to understand the ABR characters in more details. In this paper we discussed the analysis of a differ ential equation model on the latency of the 5th wave of ABR, and considered the system model of generation of the type of solution of the differential equation model on the basis of an estimation of parameters of a solution of its equation model by using the Taylor ser ies method as an iterative approximation method.