RESUMEN
The residual direct current (RDC) almost always brings serious image sticking (IS) problems in LCDs and is mainly related to the liquid crystal (LC) and photoaligned polyimide. In this paper, we propose a novel method, to the best of our knowledge, to evaluate the RDC of the FFS-LCDs through an optical measurement system. By this means, the accumulation and release of the ions can be seen distinctly through the transmittance-time curves with the voltage regulation. Hence, it is helpful to compare and analyze the RDC problem of different displays. Moreover, this method possesses the advantage of high efficiency and simplicity in order to benefit the material design in photoaligned polyimide or the LC.
RESUMEN
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Descubrimiento de Drogas , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , ortoaminobenzoatos/administración & dosificación , ortoaminobenzoatos/farmacología , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Moleculares , Conformación Molecular , Profármacos/farmacocinética , Especificidad por Sustrato , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacocinéticaRESUMEN
In the course of our Heat Shock 90 program, certain carbazole compounds were identified which had an off-target antiproliferative activity. To understand the off-target activity, we studied one analog with strong activity. We discovered that it had an effect on tubulin polymerization kinetics and was competitive with colchicine. Additional analogs were made, and a number of potent compounds were identified.
Asunto(s)
Antimitóticos/química , Carbazoles/química , Indoles/química , Antimitóticos/síntesis química , Antimitóticos/farmacología , Carbazoles/síntesis química , Carbazoles/farmacología , Línea Celular Tumoral , Colchicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Indoles/síntesis química , Indoles/farmacología , Tubulina (Proteína)/metabolismoRESUMEN
Hsp90 maintains the conformational stability of multiple proteins implicated in oncogenesis and has emerged as a target for chemotherapy. We report here the discovery of a novel small molecule scaffold that inhibits Hsp90. X-ray data show that the scaffold binds competitively at the ATP site on Hsp90. Cellular proliferation and client assays demonstrate that members of the series are able to inhibit Hsp90 at nanomolar concentrations.
Asunto(s)
Antineoplásicos/farmacología , Carbazoles/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Adenosina Trifosfato/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Unión Competitiva , Carbazoles/síntesis química , Carbazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Proteínas HSP90 de Choque Térmico/química , Humanos , Modelos Moleculares , Estructura Molecular , Peso Molecular , Bibliotecas de Moléculas Pequeñas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.