RESUMEN
Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.
RESUMEN
A kinome-wide selectivity screen of >20000 compounds with a rich representation of many structural classes has been completed. Analysis of the selectivity patterns for each class shows that a broad spectrum of structural scaffolds can achieve specificity for many kinase families. Kinase selectivity and potency are inversely correlated, a trend that is also found in a large set of kinase functional data. Although selective and nonselective compounds are mostly similar in their physicochemical characteristics, we identify specific features that are present more frequently in compounds that bind to many kinases. Our results support a scaffold-oriented approach for building compound collections to screen kinase targets.
Asunto(s)
Fosfotransferasas/antagonistas & inhibidores , Fosfotransferasas/química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad Cuantitativa , Bibliotecas de Moléculas Pequeñas , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/química , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Ensayos Analíticos de Alto Rendimiento , Unión Proteica , Homología de Secuencia de Aminoácido , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/químicaRESUMEN
Fragment-like inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK2) include 5-hydroxyisoquinoline (IC50 approximately 85 microM). Modeling studies identified four possible binding modes for this compound. Two-dimensional (1)H-(1)H NOESY data obtained with selectively protonated samples of MK2 in complex with 5-hydroxyisoquinoline demonstrated that two of the four predicted binding modes are well populated. A second small isoquinoline was subsequently shown to bind in a single mode. NMR and modeling studies using this general approach are expected to facilitate "scaffold hopping" and structure-guided elaborations of fragment-like kinase inhibitor cores.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Isoquinolinas/farmacología , Espectroscopía de Resonancia Magnética/métodos , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Isoquinolinas/química , Espectroscopía de Resonancia Magnética/normas , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Protones , Estándares de Referencia , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationships (SAR) of p38alpha MAP kinase inhibitors based on heterobicyclic scaffolds are described. This effort led to the identification of compound (21) as a potent inhibitor of p38alpha MAP kinase with good cellular potency toward the inhibition of TNF-alpha production. X-ray co-crystallography of an oxalamide analog (24) bound to unphosphorylated p38alpha is also disclosed.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacología , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Compuestos Heterocíclicos/química , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.