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1.
Bioorg Med Chem Lett ; 30(23): 127560, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-32956781

RESUMEN

The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Aberrant activation by a wide range of exogenous and endogenous signals can lead to chronic, low-grade inflammation. It has attracted a great deal of interest as a drug target due to the association with diseases of large unmet medical need such as Alzheimer's disease, Parkinson's disease, arthritis, and cancer. To date, no drugs specifically targeting inhibition of the NLRP3 inflammasome have been approved. In this work, we used the known NLRP3 inflammasome inhibitor CP-456,773 (aka CRID3 or MCC 950) as our starting point and undertook a Structure-Activity Relationship (SAR) analysis and subsequent scaffold-hopping exercise. This resulted in the rational design of a series of novel ester-substituted urea compounds that are highly potent and selective NLRP3 inflammasome inhibitors, as exemplified by compounds 44 and 45. It is hypothesized that the ester moiety acts as a highly permeable delivery vehicle and is subsequently hydrolyzed to the carboxylic acid active species by carboxylesterase enzymes. These molecules are greatly differentiated from the state-of-the-art and offer potential in the treatment of NLRP3-driven diseases, particularly where tissue penetration is required.


Asunto(s)
Ésteres/farmacología , Indenos/farmacología , Inflamasomas/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Urea/análogos & derivados , Urea/farmacología , Animales , Sangre/metabolismo , Diseño de Fármacos , Estabilidad de Medicamentos , Ésteres/síntesis química , Ésteres/metabolismo , Furanos , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Indenos/síntesis química , Indenos/metabolismo , Ratones , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas , Sulfonas/química , Células THP-1
2.
Oncotarget ; 8(20): 33779-33795, 2017 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-28422713

RESUMEN

Inhibition of oncogenic transcriptional programs is a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, is a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. X-ray crystallography has shown SEL120-34A to be a type I inhibitor forming halogen bonds with the protein's hinge region and hydrophobic complementarities within its front pocket. SEL120-34A inhibits phosphorylation of STAT1 S727 and STAT5 S726 in cancer cells in vitro. Consistently, regulation of STATs- and NUP98-HOXA9- dependent transcription has been observed as a dominant mechanism of action in vivo. Treatment with the compound resulted in a differential efficacy on AML cells with elevated STAT5 S726 levels and stem cell characteristics. In contrast, resistant cells were negative for activated STAT5 and revealed lineage commitment. In vivo efficacy in xenotransplanted AML models correlated with significant repression of STAT5 S726. Favorable pharmacokinetics, confirmed safety and in vivo efficacy provide a rationale for the further clinical development of SEL120-34A as a personalized therapeutic approach in AML.


Asunto(s)
Antineoplásicos/farmacología , Quinasa 8 Dependiente de Ciclina/antagonistas & inhibidores , Leucemia Mieloide Aguda/metabolismo , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT5/metabolismo , Animales , Antineoplásicos/química , Línea Celular Tumoral , Quinasa 8 Dependiente de Ciclina/química , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/genética , Ratones , Modelos Moleculares , Conformación Molecular , Fosforilación/efectos de los fármacos , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Factor de Transcripción STAT1/química , Factor de Transcripción STAT5/química , Ensayos Antitumor por Modelo de Xenoinjerto
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