RESUMO
[Figure: see text].
Assuntos
Insuficiência Cardíaca/metabolismo , Histona Desmetilases/metabolismo , Miofibroblastos/metabolismo , Animais , Estenose da Valva Aórtica/complicações , Células Cultivadas , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Histona Desmetilases/genética , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miofibroblastos/patologia , Ratos , Ratos Sprague-Dawley , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 µM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis.
Assuntos
Lisina , Miocárdio , Animais , Proteínas de Ligação a DNA/metabolismo , Fibrose , Isoproterenol , Histona Desmetilases com o Domínio Jumonji/metabolismo , Lisina/metabolismo , Camundongos , Miocárdio/metabolismo , Pirazóis/metabolismo , Pirazóis/farmacologia , Pirazóis/uso terapêuticoRESUMO
To discover novel anticancer agents with potent and low toxicity, we designed and synthesized a range of new thiosemicarbazone-indole analogues based on lead compound 4 we reported previously. Most compounds displayed moderate to high anticancer activities against five tested tumor cells (PC3, EC109, DU-145, MGC803, MCF-7). Specifically, the represented compound 16f possessed strong antiproliferative potency and high selectivity toward PC3 cells with the IC50 value of 0.054 µM, compared with normal WPMY-1 cells with the IC50 value of 19.470 µM. Preliminary mechanism research indicated that compound 16f could significantly suppress prostate cancer cells (PC3, DU-145) growth and colony formation in a dose-dependent manner. Besides, derivative 16f induced G1/S cycle arrest and apoptosis, which may be related to ROS accumulation due to the activation of MAPK signaling pathway. Furthermore, molecule 16f could effectively inhibit tumor growth through a xenograft model bearing PC3 cells and had no evident toxicity in vivo. Overall, based on the biological activity evaluation, analogue 16f can be viewed as a potential lead compound for further development of novel anti-prostate cancer drug.