RESUMEN
We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.
RESUMEN
Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
Asunto(s)
Adenina/análogos & derivados , Antineoplásicos/síntesis química , Indoles/síntesis química , Pirimidinas/síntesis química , Pirroles/síntesis química , eIF-2 Quinasa/antagonistas & inhibidores , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Indoles/química , Indoles/farmacología , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Trasplante de Neoplasias , Fosforilación , Conformación Proteica , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.
Asunto(s)
Amidas/síntesis química , Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Prolina/análogos & derivados , Prolina/síntesis química , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Administración Oral , Amidas/farmacología , Amidohidrolasas/metabolismo , Animales , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/crecimiento & desarrollo , Humanos , Inyecciones Intravenosas , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Prolina/farmacología , Ratas , Infecciones del Sistema Respiratorio/microbiología , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/crecimiento & desarrollo , Relación Estructura-ActividadRESUMEN
The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.
RESUMEN
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
Asunto(s)
Antineoplásicos/síntesis química , Indazoles/síntesis química , Morfolinas/síntesis química , Piperidinas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Indazoles/química , Indazoles/farmacología , Ratones , Ratones SCID , Modelos Moleculares , Estructura Molecular , Morfolinas/química , Morfolinas/farmacología , Trasplante de Neoplasias , Fosforilación , Piperidinas/química , Piperidinas/farmacología , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Estereoisomerismo , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Novel Aurora inhibitors were identified truncating clinical candidate GSK1070916. Many of these truncated compounds retained potent activity against Aurora B with good antiproliferative activity. Mechanistic studies suggested that these compounds, depending on the substitution pattern, may or may not exert their antiproliferative effects via inhibition of Aurora B. The SAR results from this investigation will be presented with an emphasis on the impact structural changes have on the cellular phenotype.
Asunto(s)
Compuestos Aza/química , Indoles/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Aurora Quinasa B , Aurora Quinasas , Línea Celular Tumoral , Descubrimiento de Drogas , Citometría de Flujo , Humanos , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
[reaction: see text] Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two stereocenters are created by the reaction, and a single isomeric product was obtained from each of the five substrates examined. The relative configurations of the products are consistent with cyclizations occurring via chairlike or pseudochairlike transition states.