RESUMO
A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35â¯has excellent CBP potency (CBP IC50â¯=â¯1â¯nM, MYC EC50â¯=â¯18â¯nM), a selectively index ofâ¯>2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.
Assuntos
Compostos de Bifenilo/química , Desenho de Fármacos , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Animais , Sítios de Ligação , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/metabolismo , Proteínas de Ciclo Celular , Cristalografia por Raios X , Meia-Vida , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
Qi-Wa refers to the up curl on the lengths of hand scrolls and hanging scrolls, which has troubled Chinese artisans and emperors for as long as the art of painting and calligraphy has existed. This warp is unwelcome not only for aesthetic reasons, but its potential damage to the fiber and ink. Although it is generally treated as a part of the cockling and curling due to moisture, consistency of paste, and defects from the mounting procedures, we demonstrate that the spontaneous extrinsic curvature incurred from the storage is in fact more essential to understanding and curing Qi-Wa. In contrast to the former factors whose effects are less predictable, the plastic deformation and strain distribution on a membrane are a well-defined mechanical problem. We study this phenomenon by experiments, theoretical models, and molecular dynamics simulation, and obtain consistent scaling relations for the Qi-Wa height. This knowledge enables us to propose modifications on the traditional mounting techniques that are tested on real mounted paper to be effective at mitigating Qi-Wa. By experimenting on polymer-based films, we demonstrate the possible relevance of our study to the modern development of flexible electronic paper.
