RESUMEN
Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridinas/química , Sitios de Unión , Cristalografía por Rayos X , Cinética , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/metabolismo , Pirazoles/química , Piridinas/síntesis química , Piridinas/metabolismo , Relación Estructura-Actividad , Sulfonas/químicaRESUMEN
Heat-shock protein 90 (Hsp90) is a molecular chaperone involved in the stabilization of key oncogenic signaling proteins, and therefore, inhibition of Hsp90 represents a new strategy in cancer therapy. 2-Amino-7-[4-fluoro-2-(3-pyridyl)phenyl]-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime is a racemic Hsp90 inhibitor that targets the N-terminal adenosine triphosphatase site. We developed a method to resolve the enantiomers and evaluated their inhibitory activity on Hsp90 and the consequent antitumor effects. The (S) stereoisomer emerged as a potent Hsp90 inhibitor in biochemical and cellular assays. In addition, this enantiomer exhibited high oral bioavailability in mice and excellent antitumor activity in two different human cancer xenograft models.
Asunto(s)
Antineoplásicos/química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Oximas/química , Quinazolinonas/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sitios de Unión , Línea Celular Tumoral , Femenino , Células HCT116 , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Ratones , Ratones Desnudos , Microsomas/metabolismo , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Oximas/farmacología , Oximas/uso terapéutico , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Estereoisomerismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.
Asunto(s)
Benzotiazoles/química , Benzotiazoles/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Benzotiazoles/síntesis química , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Ratones , Modelos Moleculares , Proteínas Tirosina Quinasas/química , Transducción de Señal , Relación Estructura-ActividadRESUMEN
PKCα and PKA have crucial but opposing roles in the regulation of calcium handling within myocytes. Identification of compounds that inhibit PKCα, but not PKA, are potential therapeutic targets for the treatment of heart disease. The synthesis of indolylureas are described, and a compound displaying nanomolar inhibition towards PKCα with significant selectivity over PKA has been identified.
Asunto(s)
Proteína Quinasa C-alfa/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Urea/síntesis química , Urea/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico , Cardiopatías/tratamiento farmacológico , Humanos , Urea/químicaAsunto(s)
Adenina/análogos & derivados , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Pirazoles/química , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Sitios de Unión , Simulación por Computador , Evaluación Preclínica de Medicamentos , Proteínas HSP90 de Choque Térmico/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , TermodinámicaRESUMEN
(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives have been investigated as potential anti-HCV drugs. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.
Asunto(s)
Antivirales/síntesis química , Azoles/síntesis química , Benzotiadiazinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Hepatitis C/tratamiento farmacológico , Piridinas/síntesis química , Pirimidinas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacología , Azoles/farmacología , Benzotiadiazinas/farmacología , Química Farmacéutica/métodos , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Hepacivirus/metabolismo , Técnicas In Vitro , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Químicos , Estructura Molecular , Piridinas/farmacología , Pirimidinas/farmacología , Relación Estructura-Actividad , Proteínas no Estructurales Virales/químicaRESUMEN
Heat shock protein 90 (Hsp90) plays a key role in stress response and protection of the cell against the effects of mutation. Herein we report the identification of an Hsp90 inhibitor identified by fragment screening using a high-concentration biochemical assay, as well as its optimisation by in silico searching coupled with a structure-based drug design (SBDD) approach.