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1.
J Pharmacol Exp Ther ; 386(2): 242-258, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37308266

RESUMEN

The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex and component of the innate immune system that is activated by exogenous and endogenous danger signals to promote activation of caspase-1 and the maturation and release of the proinflammatory cytokines interleukin (IL)-1ß and IL-18. Inappropriate activation of NLRP3 has been implicated in the pathophysiology of multiple inflammatory and autoimmune diseases, including cardiovascular disease, neurodegenerative diseases, and nonalcoholic steatohepatitis (NASH), thus increasing the clinical interest of this target. We describe in this study the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel and highly specific NLRP3 inhibitor, JT001 (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonylurea). In cell-based assays, JT001 potently and selectively inhibited NLRP3 inflammasome assembly, resulting in the inhibition of cytokine release and the prevention of pyroptosis, a form of inflammatory cell death triggered by active caspase-1. Oral administration of JT001 to mice inhibited IL-1ß production in peritoneal lavage fluid at plasma concentrations that correlated with mouse in vitro whole blood potency. Orally administered JT001 was effective in reducing hepatic inflammation in three different murine models, including the Nlrp3A350V /+CreT model of Muckle-Wells syndrome (MWS), a diet-induced obesity NASH model, and a choline-deficient diet-induced NASH model. Significant reductions in hepatic fibrosis and cell damage were also observed in the MWS and choline-deficient models. Our findings demonstrate that blockade of NLRP3 attenuates hepatic inflammation and fibrosis and support the use of JT001 to investigate the role of NLRP3 in other inflammatory disease models. SIGNIFICANCE STATEMENT: Persistent inflammasome activation is the consequence of inherited mutations of NLRP3 and results in the development of cryopyrin-associated periodic syndromes associated with severe systemic inflammation. NLRP3 is also upregulated in nonalcoholic steatohepatitis, a metabolic chronic liver disease currently missing a cure. Selective and potent inhibitors of NLRP3 hold great promise and have the potential to overcome an urgent unmet need.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas NLR , Dominio Pirina , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Caspasa 1/metabolismo , Inflamación , Colina/efectos adversos , Interleucina-1beta/metabolismo
2.
Anticancer Drugs ; 34(10): 1122-1131, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37067993

RESUMEN

Histone lysine demethylase 4 (KDM4) is an epigenetic regulator that facilitates the transition between transcriptionally silent and active chromatin states by catalyzing the removal of methyl groups on histones H3K9, H3K36, and H1.4K26. KDM4 overamplification or dysregulation has been reported in various cancers and has been shown to drive key processes linked to tumorigenesis, such as replicative immortality, evasion of apoptosis, metastasis, DNA repair deficiency, and genomic instability. KDM4 also plays a role in epigenetic regulation of cancer stem cell renewal and has been linked to more aggressive disease and poorer clinical outcomes. The KDM4 family is composed of four main isoforms (KDM4A-D) that demonstrate functional redundancy and cross-activity; thus, selective inhibition of one isoform appears to be ineffective and pan-inhibition targeting multiple KDM4 isoforms is required. Here, we describe TACH101, a novel, small-molecule pan-inhibitor of KDM4 that selectively targets KDM4A-D with no effect on other KDM families. TACH101 demonstrated potent antiproliferative activity in cancer cell lines and organoid models derived from various histologies, including colorectal, esophageal, gastric, breast, pancreatic, and hematological malignancies. In vivo , potent inhibition of KDM4 led to efficient tumor growth inhibition and regression in several xenograft models. A reduction in the population of tumor-initiating cells was observed following TACH101 treatment. Overall, these observations demonstrate the broad applicability of TACH101 as a potential anticancer agent and support its advancement into clinical trials.


Asunto(s)
Histona Demetilasas , Neoplasias , Humanos , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Histona Demetilasas/uso terapéutico , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Epigénesis Genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/uso terapéutico
3.
Bioorg Med Chem Lett ; 29(1): 103-106, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30409536

RESUMEN

The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule reversible inhibitors of LSD1 as an attractive approach to treat hematologic malignancies and certain solid tumors. Using structure-based drug design, we designed and synthesized a novel series of heteroaromatic imidazole inhibitors that demonstrate potent inhibition of the demethylase activity and low nanomolar cell-based activity. This novel LSD1 inhibitor series was further optimized by attenuating the hERG inhibition and improving oral bioavailability.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Imidazoles/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Histona Demetilasas/metabolismo , Humanos , Imidazoles/síntesis química , Imidazoles/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad
4.
Bioorg Med Chem Lett ; 28(9): 1490-1494, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29627262

RESUMEN

Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1.


Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Represoras/antagonistas & inhibidores , Proteína 2 de Unión a Retinoblastoma/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Femenino , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Modelos Moleculares , Estructura Molecular , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Proteína 2 de Unión a Retinoblastoma/metabolismo , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 28(10): 1811-1816, 2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29657099

RESUMEN

The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.


Asunto(s)
Diseño de Fármacos , Isoquinolinas/química , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Sitios de Unión , Proteínas de Ciclo Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Simulación de Dinámica Molecular , Proteínas Nucleares/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Factores de Transcripción/metabolismo
6.
Bioorg Med Chem Lett ; 27(5): 1311-1315, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-28169164

RESUMEN

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Diseño de Fármacos , Imidazoles/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/síntesis química , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Células HT29 , Xenoinjertos , Humanos , Imidazoles/química , Imidazoles/farmacología , Ratones , Estructura Molecular , Pteridinas/química , Pteridinas/farmacología , Relación Estructura-Actividad , Quinasa Tipo Polo 1
7.
J Neurosci ; 32(42): 14767-74, 2012 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-23077061

RESUMEN

Animals use gustatory information to assess the suitability of potential food sources and make critical decisions on what to consume. For example, the taste of sugar generally signals a potent dietary source of carbohydrates. However, the intensity of the sensory response to a particular sugar, or "sweetness," is not always a faithful reporter of its nutritional value, and recent evidence suggests that animals can sense the caloric content of food independently of taste. Here, we demonstrate that the vinegar fly Drosophila melanogaster uses both taste and calorie sensing to determine feeding choices, and that the relative contribution of each changes over time. Using the capillary feeder assay, we allowed flies to choose between sources of sugars that varied in their ratio of sweetness to caloric value. We found that flies initially consume sugars according to taste. However, over several hours their preference shifts toward the food source with higher caloric content. This behavioral shift occurs more rapidly following food deprivation and is modulated by cAMP and insulin signaling within neurons. Our results are consistent with the existence of a taste-independent calorie sensor in flies, and suggest that calorie-based reward modifies long-term feeding preferences.


Asunto(s)
Ingestión de Energía/fisiología , Preferencias Alimentarias/fisiología , Gusto/fisiología , Animales , Drosophila melanogaster , Femenino , Masculino
8.
Bioorg Med Chem Lett ; 23(12): 3662-6, 2013 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-23664874
9.
Sci Rep ; 13(1): 13524, 2023 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-37598239

RESUMEN

The NLRP3 inflammasome is an intracellular, multiprotein complex that promotes the auto-catalytic activation of caspase-1 and the subsequent maturation and secretion of the pro-inflammatory cytokines, IL-1ß and IL-18. Persistent activation of the NLRP3 inflammasome has been implicated in the pathophysiology of a number of inflammatory and autoimmune diseases, including neuroinflammation, cardiovascular disease, non-alcoholic steatohepatitis, lupus nephritis and severe asthma. Here we describe the preclinical profile of JT002, a novel small molecule inhibitor of the NLRP3 inflammasome. JT002 potently reduced NLRP3-dependent proinflammatory cytokine production across a number of cellular assays and prevented pyroptosis, an inflammatory form of cell death triggered by active caspase-1. JT002 demonstrated in vivo target engagement at therapeutically relevant concentrations when orally dosed in mice and prevented body weight loss and improved inflammatory and fibrotic endpoints in a model of Muckle-Wells syndrome (MWS). In two distinct models of neutrophilic airway inflammation, JT002 treatment significantly reduced airway hyperresponsiveness and airway neutrophilia. These results provide a rationale for the therapeutic targeting of the NLRP3 inflammasome in severe asthma and point to the use of JT002 in a variety of inflammatory disorders.


Asunto(s)
Enfermedades Cardiovasculares , Nefritis Lúpica , Animales , Ratones , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Caspasa 1
10.
J Med Chem ; 65(21): 14721-14739, 2022 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-36279149

RESUMEN

Inappropriate activation of the NLRP3 inflammasome has been implicated in multiple inflammatory and autoimmune diseases. Herein, we aimed to develop novel NLRP3 inhibitors that could minimize the risk of drug-induced liver injury. Lipophilic ligand efficiency was used as a guiding metric to identify a series of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinesulfonylureas. A leading compound from this series was advanced into safety studies in cynomolgus monkeys, and renal toxicity, due to compound precipitation, was observed. To overcome this obstacle, we focused on improving the solubility of our compounds, specifically by introducing basic amine substituents into the scaffold. This led to the identification of GDC-2394, a potent and selective NLRP3 inhibitor, with an in vitro and in vivo safety profile suitable for advancement into human clinical trials.


Asunto(s)
Proteína con Dominio Pirina 3 de la Familia NLR , Oxazinas , Animales , Humanos , Oxazinas/farmacología , Oxazinas/uso terapéutico , Inflamasomas , Sulfonamidas/farmacología , Macaca fascicularis
11.
J Med Chem ; 63(23): 14522-14529, 2020 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-33034194

RESUMEN

Histone demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure-activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).


Asunto(s)
Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Compuestos Orgánicos/farmacología , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Humanos , Compuestos Orgánicos/química , Relación Estructura-Actividad
12.
Mol Cancer Ther ; 6(7): 2012-21, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17620431

RESUMEN

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Indazoles/farmacología , Indazoles/farmacocinética , Neovascularización Patológica/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacología , Pirimidinas/farmacocinética , Sulfonamidas/farmacología , Sulfonamidas/farmacocinética , Sulfonas/farmacología , Sulfonas/farmacocinética , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Línea Celular Tumoral , Sistema Libre de Células , Córnea/patología , Relación Dosis-Respuesta a Droga , Femenino , Factor 2 de Crecimiento de Fibroblastos/farmacología , Humanos , Indazoles/administración & dosificación , Indazoles/sangre , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Fosforilación/efectos de los fármacos , Fosfotirosina/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/sangre , Pirimidinas/administración & dosificación , Pirimidinas/sangre , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Sulfonamidas/administración & dosificación , Sulfonamidas/sangre , Sulfonas/administración & dosificación , Sulfonas/sangre , Factor A de Crecimiento Endotelial Vascular/farmacología
14.
J Med Chem ; 50(10): 2297-300, 2007 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-17441705

RESUMEN

Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase III trials in patients with type 2 diabetes.


Asunto(s)
Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV , Hipoglucemiantes/síntesis química , Piperidinas/síntesis química , Pirimidinonas/síntesis química , Quinazolinonas/síntesis química , Uracilo/análogos & derivados , Animales , Sitios de Unión , Glucemia/análisis , Inhibidores Enzimáticos del Citocromo P-450 , Diabetes Mellitus Experimental/tratamiento farmacológico , Perros , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Haplorrinos , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Técnicas In Vitro , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacología , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Quinazolinonas/farmacocinética , Quinazolinonas/farmacología , Ratas , Ratas Wistar , Relación Estructura-Actividad , Uracilo/síntesis química , Uracilo/farmacocinética , Uracilo/farmacología
15.
Cancer Res ; 77(21): 5900-5912, 2017 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28883001

RESUMEN

Traditional treatments for breast cancer fail to address therapy-resistant cancer stem-like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem-like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Cancer Res; 77(21); 5900-12. ©2017 AACR.


Asunto(s)
Proliferación Celular/genética , Histona Demetilasas con Dominio de Jumonji/genética , Células Madre Neoplásicas/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Animales , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Ratones Endogámicos NOD , Ratones SCID , Estructura Molecular , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Interferencia de ARN , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
16.
ACS Med Chem Lett ; 8(8): 869-874, 2017 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-28835804

RESUMEN

Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.

17.
Oncogene ; 24(5): 790-800, 2005 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-15592523

RESUMEN

Cancer growth and progression is often critically influenced by the production of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis. VEGF produced by tumor cells stimulates endothelial cell growth through the binding and activation of the KDR/Flk-1 receptor (VEGFR-2) on endothelial cells. Recently, some human breast cancer epithelial cells have been shown to express VEGF receptors, suggesting a potential autocrine-mediated growth stimulation of a subset of cancers by VEGF. We demonstrate that mammary tumors in the C3(1)/Tag transgenic model express VEGF and VEGF receptors and tumor growth is stimulated by this autocrine mechanism. GW654652, an indazolylpyrimidine, is a VEGFRs tyrosine kinase inhibitor that dramatically reduces both angiogenesis and tumor cell growth in this model, as demonstrated using both in vitro and in vivo assays. GW654652 significantly decreased cell proliferation and induced apoptosis in human umbilical vein endothelial cells and M6 mammary tumor cells derived from C3(1)/Tag (Tag: simian virus 40 T-antigen) transgenic mice. A 75% reduction in VEGF-induced angiogenesis was observed with GW654652 using the chick chorioallantoic membrane assay, whereas GW654652 produced an approximately 85% reduction in angiogenesis as assessed by the Matrigel plug assay. A profound inhibitory effect on tumor growth in the C3(1)/Tag transgenic model of human breast cancer was observed with oral administration of GW654652 as measured by delayed tumor onset, decreased multiplicity, reduced tumor volume, and extended animal survival. The antitumor effects of GW654652 were associated with reduced tumor vascularization and no apparent toxicity. Tumor growth, however, rapidly advanced following cessation of treatment. This is the first demonstration that a VEGF receptor inhibitor, GW654652, has a strong inhibitory effect on angiogenesis and tumor progression in a transgenic model of mammary cancer, suggesting that this is a useful approach for preclinical testing of such agents.


Asunto(s)
Neoplasias Mamarias Animales/patología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Alantoides/citología , Animales , Antígenos Transformadores de Poliomavirus/genética , Antineoplásicos/toxicidad , Apoptosis , División Celular/efectos de los fármacos , Corion/citología , Cartilla de ADN , Endotelio Vascular/citología , Femenino , Citometría de Flujo , Humanos , Imidazoles/farmacología , Ratones , Ratones Transgénicos , Neovascularización Patológica/patología , Neovascularización Fisiológica/efectos de los fármacos , Pirimidinas/farmacología , ARN Interferente Pequeño/genética , Receptores de Factores de Crecimiento Endotelial Vascular/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección , Venas Umbilicales , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética
18.
J Med Chem ; 48(5): 1610-9, 2005 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-15743202

RESUMEN

A series of derivatives of 2-anilino-5-phenyloxazole (5) has been identified as inhibitors of VEGFR2 kinase. Herein we describe the structure-activity relationship (SAR) of this novel template. Optimization of both aryl rings led to very potent inhibitors at both the enzymatic and cellular levels. Oxazole 39 had excellent solubility and good oral PK when dosed as the bis-mesylate salt and demonstrated moderate in vivo efficacy against HT29 human colon tumor xenografts. X-ray crystallography confirmed the proposed binding mode, and comparison of oxazoles 39 and 46 revealed interesting differences in orientation of 2-pyridyl and 3-pyridyl rings, respectively, attached at the meta position of the 5-phenyl ring.


Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Compuestos de Anilina/síntesis química , Oxazoles/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adenosina Trifosfato/química , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Compuestos de Anilina/farmacocinética , Compuestos de Anilina/farmacología , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cristalografía por Rayos X , Perros , Humanos , Ligandos , Masculino , Ratones , Modelos Moleculares , Oxazoles/farmacocinética , Oxazoles/farmacología , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad , Venas Umbilicales/citología , Factor A de Crecimiento Endotelial Vascular/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química , Ensayos Antitumor por Modelo de Xenoinjerto
19.
J Med Chem ; 54(2): 510-24, 2011 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-21186796

RESUMEN

The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.


Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Pirimidinonas/síntesis química , Animales , Sitios de Unión , Disponibilidad Biológica , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Macaca fascicularis , Modelos Moleculares , Pirimidinonas/química , Pirimidinonas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad
20.
J Med Chem ; 51(15): 4632-40, 2008 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-18620382

RESUMEN

Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.


Asunto(s)
Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Sulfonamidas/química , Sulfonamidas/farmacología , Animales , Células Cultivadas , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Indazoles , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Ratones , Modelos Moleculares , Estructura Molecular , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/química , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Sulfonamidas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
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