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1.
J Pharmacol Exp Ther ; 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39284624

RESUMEN

We previously identified a small molecule, UM101, predicted to bind to the substrate-binding groove of p38aMitogen-activated Protein Kinase (MAPK) near the binding site of its proinflammatory substrate, MAPK-activated protein kinase (MK2). UM101 exhibited anti-inflammatory, endothelial-stabilizing, and lung-protective effects. To overcome its limited aqueous solubility and p38a binding affinity, we designed an analog of UM101, GEn-1124, with improved aqueous solubility, stability, and p38a binding affinity. Compared with UM101, GEn-1124 has 18-fold greater p38a-binding affinity as measured by Surface Plasmon Resonance (SPR), 11-fold greater aqueous solubility, enhanced barrier-stabilizing activity in thrombin-stimulated human pulmonary artery endothelial cells (hPAEC) in vitro, and greater lung protection in vivo GEn-1124 improved survival from 10% to 40% in murine acute lung injury (ALI) induced by combined exposure to intratracheal bacterial endotoxin lipopolysaccharide (LPS) instillation and febrile-range hyperthermia (FRH) and from 0% to 50% in a mouse influenza pneumonia model. Gene expression analysis by RNASeq in TNFa-treated hPAEC showed that the gene-modifying effects of GEn-1124 were much more restricted to TNFa-inducible genes than the catalytic site p38 inhibitor, SB203580. Gene expression pathway analysis, confocal immunofluorescence analysis of p38aand MK2 subcellular trafficking, and SPR analysis of phosphorylated p38a:MK2 binding affinity supports a novel mechanism of action. GEn-1124 destabilizes the activated p38a:MK2 complex, dissociates nuclear export of MK2 and p38a, thereby promoting intranuclear retention and enhanced intranuclear signaling by phosphorylated p38a retention, and accelerated inactivation of p38-free cytosolic MK2 by unopposed phosphatases. Significance Statement We describe an analog of our first-in-class small molecule modulator of p38a/MK2 signaling targeted to a pocket near the ED substrate binding domain of p38a, which destabilizes the p38a:MK2 complex without blocking p38 catalytic activity or ablating downstream signaling. The result is a rebalancing of downstream pro- and anti-inflammatory signaling, yielding anti-inflammatory, endothelial-stabilizing, and lung-protective effects with therapeutic potential in ARDS.

2.
Bioorg Med Chem Lett ; 22(11): 3732-8, 2012 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-22542012

RESUMEN

A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.


Asunto(s)
Diseño de Fármacos , Furanos/química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Pirimidinonas/química , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Relación Estructura-Actividad
3.
Bioorg Med Chem Lett ; 22(11): 3727-31, 2012 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-22560567

RESUMEN

CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacocinética , Animales , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Simulación por Computador , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Pirimidinonas/uso terapéutico , Ratas , Relación Estructura-Actividad , Trasplante Heterólogo , Regulación hacia Arriba
4.
Bioorg Med Chem Lett ; 22(24): 7653-8, 2012 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-23127890

RESUMEN

We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.


Asunto(s)
Antineoplásicos/farmacología , Janus Quinasa 2/antagonistas & inhibidores , Neoplasias Experimentales/tratamiento farmacológico , Prolina/análogos & derivados , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Ensayos Analíticos de Alto Rendimiento , Janus Quinasa 2/metabolismo , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/patología , Prolina/administración & dosificación , Prolina/química , Prolina/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Bioorg Med Chem Lett ; 21(22): 6773-7, 2011 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-21974949

RESUMEN

A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo.


Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Glucosiltransferasas/metabolismo , Administración Oral , Animales , Descubrimiento de Drogas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratones , Ratones Endogámicos C57BL , Relación Estructura-Actividad
6.
J Med Chem ; 55(9): 4322-35, 2012 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-22497444

RESUMEN

Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC(50) of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.


Asunto(s)
Inhibidores Enzimáticos/síntesis química , Glucosiltransferasas/antagonistas & inhibidores , Fenilalanina/análogos & derivados , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/enzimología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Gangliósidos/metabolismo , Prueba de Tolerancia a la Glucosa , Glucosiltransferasas/metabolismo , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Fenilalanina/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Relación Estructura-Actividad , Triglicéridos/sangre
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