RESUMEN
Toll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase 1 clinical trials.
RESUMEN
A simple and rapid capillary electrophoresis (CE) with electrcochemical detection (ED) method has been established for the simultaneous determination of seven active ingredients in the stems and roots of Gaultheria leucocarpa var. yunnanensis and its medicinal preparation, including (+)-catechin, rutin, gentisic acid, vallinic acid, salicylic acid, quercetin, and protocatechuic acid. The effects of working potential, pH, and concentration of running buffer, separation voltage, and injection time on CE-ED are systematically investigated. Under the optimum conditions, the seven analytes could be completely separated within 23 min in a borax running buffer (pH 8.7). A good linear relationship is obtained over three orders of magnitude with detection limits (signal-to-noise ratio=3) ranging from 5x10(-8) g/mL to 3x10(-7) g/mL for the analytes. The proposed method is successfully used in the analysis of real samples after a relatively simple extraction procedure, and the assay results are satisfactory.
Asunto(s)
Electroforesis Capilar/métodos , Gaultheria/química , Preparaciones de Plantas/análisis , Catequina/análisis , Electroquímica/métodos , Gentisatos/análisis , Concentración de Iones de Hidrógeno , Hidroxibenzoatos/análisis , Raíces de Plantas/química , Tallos de la Planta/química , Quercetina/análisis , Reproducibilidad de los Resultados , Rutina/análisis , Ácido Salicílico/análisis , Sensibilidad y Especificidad , Ácido Vanílico/análogos & derivados , Ácido Vanílico/análisisRESUMEN
A method based on capillary electrophoresis with electrochemical detection has been developed for the separation and determination of isovanillic acid, gentisic acid, kaempferol, quercetin, caffeic acid and protocatechuic acid in Ilex Purpurea Hassk and its medicinal preparations for the first time. The effects of working electrode potential, pH and concentration of running buffer, separation voltage and injection time on CE-ED were investigated. Under the optimum conditions, the analytes could be separated in a 50 mmoll(-1) borate buffer (pH 9.0) within 21 min. A 300 microm diameter carbon disk electrode has a good response at +0.95 V (versus SCE) for all analytes. The response was linear over three orders of magnitude with detection limits (S/N=3) ranging from 3 x 10(-8) to 2 x 10(-7)gml(-1) for the analytes. The method has been successfully applied to the analysis of real sample, with satisfactory results.