RESUMEN
Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.
Asunto(s)
Proteínas de la Membrana/agonistas , Nucleótidos Cíclicos/química , Pirimidinas/química , Administración Intravenosa , Animales , Sitios de Unión , Línea Celular Tumoral , Semivida , Humanos , Inmunoterapia , Proteínas de la Membrana/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Neoplasias/patología , Neoplasias/terapia , Nucleótidos Cíclicos/metabolismo , Nucleótidos Cíclicos/uso terapéutico , Fosfatos/química , Ratas , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.
Asunto(s)
Antineoplásicos/síntesis química , Benzazepinas/síntesis química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Lactamas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Tionas/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzazepinas/farmacocinética , Benzazepinas/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactamas/farmacocinética , Lactamas/farmacología , Ratones , Ratones Desnudos , Mitosis , Modelos Moleculares , Trasplante de Neoplasias , Conformación Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tionas/farmacocinética , Tionas/farmacología , Trasplante Heterólogo , Quinasa Tipo Polo 1RESUMEN
Inhibitors of IkappaB kinase (IKK) have long been sought as specific regulators of NF-kappaB. A screening effort of the endogenous IKK complex allowed us to identify 5-bromo-6-methoxy-beta-carboline as a nonspecific IKK inhibitor. Optimization of this beta-carboline natural product derivative resulted in a novel class of selective IKK inhibitors with IC(50)s in the nanomolar range. In addition, we show that one of these beta-carboline analogues inhibits the phosphorylation of IkappaBalpha and subsequent activation of NF-kappaB in whole cells, as well as blocking TNF-alpha release in LPS-challenged mice.