RESUMEN
The structure-based design and optimization of a novel series of selective PERK inhibitors are described resulting in the identification of 44 as a potent, highly selective, and orally active tool compound suitable for PERK pathway biology exploration both in vitro and in vivo.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , eIF-2 Quinasa/antagonistas & inhibidores , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , eIF-2 Quinasa/metabolismoRESUMEN
The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Triazinas/farmacología , Cristalografía por Rayos X , Modelos Moleculares , Inhibidores de Proteínas Quinasas/químicaRESUMEN
A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Piperazinas/síntesis química , Piridinas/síntesis química , Sulfonamidas/síntesis química , Triazinas/síntesis química , Animales , Disponibilidad Biológica , Fosfatidilinositol 3-Quinasa Clase I/fisiología , Cristalografía por Rayos X , Diseño de Fármacos , Femenino , Humanos , Indazoles/síntesis química , Indazoles/farmacocinética , Indazoles/farmacología , Ratones , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperazinas/farmacocinética , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-akt/fisiología , Purinas/síntesis química , Purinas/farmacocinética , Purinas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacocinética , Pirazoles/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Transducción de Señal , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Sulfonas/síntesis química , Sulfonas/farmacocinética , Sulfonas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Triazinas/farmacocinética , Triazinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound 59e (AMG 458) was ultimately advanced into preclinical safety studies.
Asunto(s)
Aminopiridinas/síntesis química , Antineoplásicos/síntesis química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirazoles/síntesis química , Aminopiridinas/química , Aminopiridinas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Gastrinas/metabolismo , Humanos , Masculino , Ratones , Modelos Moleculares , Fosforilación , Conformación Proteica , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirazoles/química , Pirazoles/farmacología , Pirazolonas/síntesis química , Pirazolonas/química , Pirazolonas/farmacología , Ratas , Receptor IGF Tipo 1/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity.
Asunto(s)
Antineoplásicos/síntesis química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirazolonas/síntesis química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Fosforilación , Conformación Proteica , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirazolonas/farmacocinética , Pirazolonas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor IGF Tipo 1/antagonistas & inhibidores , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Phosphoinositide 3-kinase α (PI3Kα) is a lipid kinase that plays a key regulatory role in several cellular processes. The mutation or amplification of this kinase in humans has been implicated in the growth of multiple tumor types. Consequently, PI3Kα has become a target of intense research for drug discovery. Our studies began with the identification of benzothiazole compound 1 from a high throughput screen. Extensive SAR studies led to the discovery of sulfonamide 45 as an early lead, based on its in vitro cellular potency. Subsequent modifications of the central pyrimidine ring dramatically improved enzyme and cellular potency and led to the identification of chloropyridine 70. Further arylsulfonamide SAR studies optimized in vitro clearance and led to the identification of 82 as a potent dual inhibitor of PI3K and mTOR. This molecule exhibited potent enzyme and cell activity, low clearance, and high oral bioavailability. In addition, compound 82 demonstrated tumor growth inhibition in U-87 MG, A549, and HCT116 tumor xenograft models.
Asunto(s)
Antineoplásicos/síntesis química , Benzotiazoles/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Sulfonamidas/síntesis química , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Benzotiazoles/química , Benzotiazoles/farmacología , Sitios de Unión , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Desnudos , Modelos Moleculares , Trasplante de Neoplasias , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Trasplante HeterólogoRESUMEN
c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.