RESUMEN
Aurora kinase A, a mitotic kinase that is overexpressed in various cancers, is a promising cancer drug target. Here, we performed preclinical characterization of TAS-119, a novel, orally active, and highly selective inhibitor of Aurora A. TAS-119 showed strong inhibitory effect against Aurora A, with an IC50 value of 1.04 nmol/L. The compound was highly selective for Aurora A compared with 301 other protein kinases, including Aurora kinase B. TAS-119 induced the inhibition of Aurora A and accumulation of mitotic cells in vitro and in vivo. It suppressed the growth of various cancer cell lines harboring MYC family amplification and CTNNB1 mutation in vitro. In a xenograft model of human lung cancer cells harboring MYC amplification and CTNNB1 mutation, TAS-119 showed a strong antitumor activity at well-tolerated doses. TAS-119 induced N-Myc degradation and inhibited downstream transcriptional targets in MYCN-amplified neuroblastoma cell lines. It also demonstrated inhibitory effect against tropomyosin receptor kinase (TRK)A, TRKB, and TRKC, with an IC50 value of 1.46, 1.53, and 1.47 nmol/L, respectively. TAS-119 inhibited TRK-fusion protein activity and exhibited robust growth inhibition of tumor cells via a deregulated TRK pathway in vitro and in vivo. Our study indicates the potential of TAS-119 as an anticancer drug, especially for patients harboring MYC amplification, CTNNB1 mutation, and NTRK fusion.
Asunto(s)
Antineoplásicos , Aurora Quinasa A , Neoplasias Pulmonares , Piperidinas , Inhibidores de Proteínas Quinasas , Receptor trkA , Carcinoma Pulmonar de Células Pequeñas , Animales , Humanos , Masculino , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/metabolismo , beta Catenina/genética , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones Desnudos , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptor trkA/antagonistas & inhibidores , Receptor trkA/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Carga Tumoral/efectos de los fármacos , Piperidinas/farmacología , Piperidinas/uso terapéuticoRESUMEN
This Letter describes the synthesis and evaluation of mGluR7 antagonists in the isoxazolopyridone series. In the course of modification in this class, novel solid support synthesis of the isoxazolopyridone scaffold was developed. Subsequent chemical modification led to the identification of several potent derivatives with improved physicochemical properties compared to a hit compound 1. Among these, 2 showed good oral bioavailability and brain penetrability, suggesting that 2 may be useful for in vivo study to elucidate the role of mGluR7.
Asunto(s)
Isoxazoles/química , Piridonas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Regulación Alostérica , Animales , Encéfalo/metabolismo , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Piridonas/síntesis química , Piridonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
The identification and structure-activity-relationships (SARs) of novel 2-amino benzamide glucokinase activators are described. Compounds in this series were developed to be potent GK activators, and their binding mode to the GK protein was determined by crystal structure analysis. In vivo pharmacokinetic and acute in vivo efficacy studies of compound 18 are also described.
Asunto(s)
Benzamidas/química , Glucoquinasa/metabolismo , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Animales , Benzamidas/farmacología , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Masculino , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
A novel class of 3,6-disubstituted 2-pyridinecarboxamide derivatives was designed based on X-ray analysis of the 2-aminobenzamide lead class. Subsequent chemical modification led to the discovery of potent GK activators which eliminate potential toxicity concerns associated with an aniline group of the lead structure. Compound 7 demonstrated glucose lowering effect in a rat OGTT model.
Asunto(s)
Amidas/química , Glucoquinasa/metabolismo , Hipoglucemiantes/química , Piridinas/química , Amidas/síntesis química , Amidas/farmacocinética , Animales , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Glucoquinasa/química , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
We describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d).
Asunto(s)
Glucoquinasa/química , Hipoglucemiantes/química , Quinazolinas/química , Animales , Glucemia/análisis , Descubrimiento de Drogas , Glucoquinasa/metabolismo , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Ratones , Quinazolinas/síntesis química , Quinazolinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.
Asunto(s)
Antineoplásicos/química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Piridinas/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Simulación por Computador , Células HeLa , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Modelos Químicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasa Tipo Polo 1RESUMEN
Glucokinase is a monomeric enzyme that displays a low affinity for glucose and a sigmoidal saturation curve for its substrate, two properties that are important for its playing the role of a glucose sensor in pancreas and liver. The molecular basis for these two properties is not well understood. Herein we report the crystal structures of glucokinase in its active and inactive forms, which demonstrate that global conformational change, including domain reorganization, is induced by glucose binding. This suggests that the positive cooperativity of monomeric glucokinase obeys the "mnemonical mechanism" rather than the well-known concerted model. These structures also revealed an allosteric site through which small molecules may modulate the kinetic properties of the enzyme. This finding provided the mechanistic basis for activation of glucokinase as a potential therapeutic approach for treating type 2 diabetes mellitus.
Asunto(s)
Glucoquinasa/química , Glucoquinasa/metabolismo , Regulación Alostérica/fisiología , Sitios de Unión , Dominio Catalítico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/uso terapéutico , Glucoquinasa/genética , Hexoquinasa/química , Hexoquinasa/genética , Hexoquinasa/metabolismo , Humanos , Modelos Moleculares , Mutación , Conformación ProteicaRESUMEN
Novel isoxazolopyridone derivatives that are metabotropic glutamate receptor (mGluR) 7 antagonists were discovered and pharmacologically characterized. 5-Methyl-3,6-diphenylisoxazolo[4,5-c]pyridin-4(5H)-one (MDIP) was identified by random screening, and 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) was produced by chemical modification of MDIP. MDIP and MMPIP inhibited L-(+)-2-amino-4-phosphonobutyric acid (L-AP4)-induced intracellular Ca2+ mobilization in Chinese hamster ovary (CHO) cells coexpressing rat mGluR7 with Galpha(15) (IC50 = 20 and 26 nM). The maximal response in agonist concentration-response curves was reduced in the presence of MMPIP, and its antagonism is reversible. MMPIP did not displace [3H](2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495) bound to mGluR7. These results suggested that these isoxazolopyridone derivatives are allosteric antagonists. In CHO cells expressing rat mGluR7, MDIP and MMPIP inhibited l-AP4-induced inhibition of forskolin-stimulated cAMP accumulation (IC50 = 99 and 220 nM). In CHO cells coexpressing human mGluR7 with Galpha(15), MDIP and MMPIP also inhibited the l-AP4-induced cAMP response. The maximal degree of inhibition by MMPIP was higher than that by MDIP in a cAMP assay. MMPIP was able to antagonize an allosteric agonist, the N,N'-dibenzhydryl-ethane-1,2-diamine dihydrochloride (AMN082)-induced inhibition of cAMP accumulation. In the absence of these agonists, MMPIP caused a further increase in forskolin-stimulated cAMP levels in CHO cells expressing mGluR7, whereas a competitive antagonist, LY341495, did not. This result indicates that MMPIP has an inverse agonistic activity. The intrinsic activity of MMPIP was pertussis toxin-sensitive and mGluR7-dependent. MMPIP at concentrations of at least 1 microM had no significant effect on mGluR1, mGluR2, mGluR3, mGluR4, mGluR5, and mGluR8. MMPIP is the first allosteric mGluR7-selective antagonist that could potentially be useful as a pharmacological tool for elucidating the roles of mGluR7 on central nervous system functions.
Asunto(s)
Oxazoles/farmacología , Piridonas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Proteínas Recombinantes/antagonistas & inhibidores , Sitio Alostérico , Animales , Unión Competitiva , Células CHO , Calcio/metabolismo , Clonación Molecular , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Oxazoles/química , Piridonas/química , ARN Interferente Pequeño/farmacología , Ratas , Receptores de Glutamato Metabotrópico/biosíntesisRESUMEN
Synthesis and structure-activity relationship of a new class of muscarinic M(3) selective antagonists were described. In the course of searching for a muscarinic M(3) antagonist with a structure distinct from those of the 2-(4,4-difluorocyclopentyl)-2-phenylacetamide derivatives, we identified a thiazole-4-carboxamide derivative (1) as a lead compound in our in-house chemical collection. Since this compound (1) showed relatively low binding affinity (K(i)=140 nM) for M(3) receptors in the human binding assays, we tried to improve its potency and selectivity for M(3) over M(1) and M(2) receptors by derivatization of 1 through a combinatorial approach. A solution-phase parallel synthesis effectively contributed to the optimization of each segment of 1. Thus, we have identified a cyclooctenylmethyl derivative (3e) and a cyclononenylmethyl derivative (3f) as representative M(3) selective antagonists in this class.