Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
J Pharmacol Exp Ther ; 388(3): 813-826, 2024 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-38336379

RESUMEN

Systemic and cerebral inflammatory responses are implicated in the pathogenesis of obesity and associated metabolic impairment. While the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to obesity-associated inflammation, whether it contributes to the development or maintenance of obesity is unknown. We provide support for a direct role of saturated fatty acids, such as palmitic acid, as NLRP3 activating stimuli in obese states. To investigate whether NLRP3 activation contributes to the pathogenesis of diet-induced obesity (DIO) in mice, we tested two different clinical-stage NLRP3 inflammasome inhibitors. We demonstrate a contributory role of this key inflammasome to established obesity and associated systemic and cerebral inflammation. By comparing their effects to calorie restriction, we aimed to identify specific NLRP3-sensitive mechanisms contributing to obesity-induced inflammation (as opposed to be those regulated by weight loss per se). In addition, a direct comparison of an NLRP3 inhibitor to a glucagon like peptide-1 receptor agonist, semaglutide (Wegovy), in the DIO model allowed an appreciation of the relative efficacy of these two therapeutic strategies on obesity, its associated systemic inflammatory response, and cerebral gliosis. We show that two structurally distinct, NLRP3 inhibitors, NT-0249 and NT-0796, reverse obesity in the DIO mouse model and that brain exposure appears necessary for efficacy. In support of this, we show that DIO-driven hypothalamic glial fibrillary acidic protein expression is blocked by dosing with NT-0249/NT-0796. While matching weight loss driven by semaglutide or calorie restriction, remarkably, NLRP3 inhibition provided enhanced improvements in disease-relevant biomarkers of acute phase response, cardiovascular inflammation, and lipid metabolism. SIGNIFICANCE STATEMENT: Obesity is a global health concern that predisposes individuals to chronic disease such as diabetes and cardiovascular disease at least in part by promoting systemic inflammation. We report that in mice fed a high-fat, obesogenic diet, obesity is reversed by either of two inhibitors of the intracellular inflammatory mediator NLRP3. Furthermore, NLRP3 inhibition reduces both hypothalamic gliosis and circulating biomarkers of cardiovascular disease risk beyond what can be achieved by either the glucagon like peptide-1 agonist semaglutide or calorie restriction alone.


Asunto(s)
Enfermedades Cardiovasculares , Inflamasomas , Ratones , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Gliosis/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos NOD , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Obesidad/metabolismo , Pérdida de Peso , Biomarcadores , Péptidos Similares al Glucagón , Ratones Endogámicos C57BL
2.
J Med Chem ; 64(18): 13524-13539, 2021 09 23.
Artículo en Inglés | MEDLINE | ID: mdl-34478292

RESUMEN

Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.


Asunto(s)
Antineoplásicos/uso terapéutico , Imidazoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Imidazoles/síntesis química , Masculino , Ratones Endogámicos C57BL , Ratones Desnudos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas/metabolismo , Piridinas/síntesis química , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Tirosina Quinasa c-Mer/metabolismo , Tirosina Quinasa del Receptor Axl
3.
Mol Cancer Ther ; 20(2): 238-249, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33273059

RESUMEN

The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF-mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS-mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signaling in KRAS-mutant tumors and achieve meaningful clinical benefit. Here, we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro, AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF-mutant and KRAS-mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose- and time-dependent modulation of ERK1/2-dependent signaling biomarkers resulting in tumor regression in sensitive BRAF- and KRAS-mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor, selumetinib (AZD6244 and ARRY142886), enhances efficacy in KRAS-mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signaling pathway that is not achievable with single-agent treatment. The AZD0364 and selumetinib combination also results in significant tumor regressions in multiple KRAS-mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS-mutant tumors.


Asunto(s)
Bencimidazoles/uso terapéutico , Imidazoles/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Pirazinas/uso terapéutico , Pirimidinas/uso terapéutico , Animales , Bencimidazoles/farmacología , Modelos Animales de Enfermedad , Humanos , Imidazoles/farmacología , Ratones , Ratones Desnudos , Pirazinas/farmacología , Pirimidinas/farmacología
4.
J Med Chem ; 62(24): 11004-11018, 2019 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-31710489

RESUMEN

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Descubrimiento de Drogas , Imidazoles/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/uso terapéutico , Pirimidinas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Quimioterapia Combinada , Femenino , Humanos , Imidazoles/farmacología , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazinas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
5.
J Med Chem ; 62(21): 9918-9930, 2019 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-31622099

RESUMEN

In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.


Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Terapia Molecular Dirigida , Factor 88 de Diferenciación Mieloide/genética , Quinazolinas/química , Quinazolinas/farmacología , Administración Oral , Animales , Línea Celular Tumoral , Diseño de Fármacos , Femenino , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/química , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Ratones , Modelos Moleculares , Mutación , Conformación Proteica , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/administración & dosificación , Quinazolinas/farmacocinética , Ratas , Ratas Wistar , Relación Estructura-Actividad , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Bioorg Med Chem ; 26(4): 913-924, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29398441

RESUMEN

We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.


Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Pirroles/química , Tiazinas/química , Animales , Sitios de Unión , Células CACO-2 , Perros , Diseño de Fármacos , Semivida , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Simulación de Dinámica Molecular , Mutación , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Permeabilidad/efectos de los fármacos , Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Relación Estructura-Actividad , Tiazinas/farmacocinética , Tiazinas/farmacología
7.
J Med Chem ; 60(24): 10071-10091, 2017 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-29172502

RESUMEN

Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.


Asunto(s)
Antineoplásicos/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Femenino , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/química , Linfoma de Células B Grandes Difuso/genética , Espectroscopía de Resonancia Magnética , Masculino , Ratones SCID , Mutación , Factor 88 de Diferenciación Mieloide/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/química , Pirroles/química , Ratas Wistar , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
8.
J Med Chem ; 60(8): 3438-3450, 2017 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-28376306

RESUMEN

There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.


Asunto(s)
Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Perros , Descubrimiento de Drogas , Humanos , Metilación , Inhibidores de Proteínas Quinasas/farmacocinética
9.
Nat Chem Biol ; 12(6): 444-51, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27110679

RESUMEN

Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1(N48K) that involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1(N48K), followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure-activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.


Asunto(s)
Modelos Animales de Enfermedad , Proteínas de la Membrana/antagonistas & inhibidores , Pirazoles/farmacología , Piridazinas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Síndromes de Usher/tratamiento farmacológico , Animales , Ensayos Analíticos de Alto Rendimiento , Humanos , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/uso terapéutico , Piridazinas/síntesis química , Piridazinas/química , Piridazinas/uso terapéutico , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Síndromes de Usher/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...