RESUMEN
Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(V600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(V600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
RESUMEN
A potent series of inhibitors against the B-Raf(V600E) kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamide nitrogen.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sulfonamidas/química , Administración Oral , Sustitución de Aminoácidos , Animales , Sitios de Unión , Dominio Catalítico , Flúor/química , Microsomas Hepáticos/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
The scope of Pd-catalyzed synthesis of N-Boc-protected anilines from aryl bromides and commercially available tert-butyl carbamate is described. For the first time, this process can be conducted at room temperature (17-22 degrees C) using a combination of Pd(2)dba(3).CHCl(3) and a monodentate ligand, tert-butyl X-Phos. Use of sodium tert-butoxide is crucial to the success of the reaction, which proceeds in 43-83% yield.
Asunto(s)
Compuestos de Anilina/síntesis química , Bromobencenos/química , Carbamatos/química , Catálisis , Compuestos Organometálicos/química , Paladio/química , TemperaturaRESUMEN
A series of thiophene PLK1 inhibitors was optimized for increased solubility and reduced protein binding through the appendage of basic amine functionality. Interesting selectivity between PLK1 and PLK3 was also obtained through these modifications.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Química Farmacéutica/métodos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Tiofenos/química , Ciclo Celular , Proteínas de Ciclo Celular/química , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Mitosis , Modelos Químicos , Conformación Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/química , Proteínas Proto-Oncogénicas/química , Solubilidad , Proteínas Supresoras de Tumor , Quinasa Tipo Polo 1RESUMEN
A 15-member library of phosphaadamantane ligands has been prepared via P-arylation of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phosphaadamantane. Screening of this tertiary phosphine collection has allowed for the rapid determination of the most suitable ligand, specifically 1,3,5,7-tetramethyl-6-(2,4-dimethoxyphenyl)-2,4,8-trioxa-6-phosphaadamantane, for facilitating Suzuki-type couplings of alkyl halides or tosylates containing beta-hydrogens with either boronic acids or alkylboranes.