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Org Biomol Chem ; 22(26): 5374-5384, 2024 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-38869445

RESUMEN

The success of targeted covalent inhibitors (TCIs) for treating cancers has spurred the search for novel scaffolds to install covalent warheads. In our endeavour, using a scaffold hopping strategy, we managed to utilize imidazo[1,2-a]pyridine as the core backbone and explored its potential for the development of covalent inhibitors, therefore, synthesizing a series of novel KRAS G12C inhibitors facilitated by the Groebke-Blackburn-Bienaymè reaction (GBB reaction). Preliminary bio-evaluation screening delivered compound I-11 as a potent anticancer agent for KRAS G12C-mutated NCI-H358 cells, whose effects were further clarified by a series of cellular, biochemical, and molecular docking experiments. These results not only indicate the potential of compound I-11 as a lead compound for the treatment of intractable cancers, but also validate the unique role of imidazo[1,2-a]pyridine as a novel scaffold suitable for the discovery of covalent anticancer agents.


Asunto(s)
Antineoplásicos , Descubrimiento de Drogas , Piridinas , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Humanos , Piridinas/farmacología , Piridinas/química , Piridinas/síntesis química , Línea Celular Tumoral , Imidazoles/química , Imidazoles/farmacología , Imidazoles/síntesis química , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a Droga
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