RESUMEN
Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild-type RET (wt RET) and its mutants (e.g., V804M RET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wt RET/V804M RET inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N'-{4'-[(2''-benzamido)pyridin-4''-ylamino]phenyl}urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/wt RET/V804M RET inhibitor.
Asunto(s)
Aminopiridinas/química , Compuestos de Fenilurea/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-ret/metabolismo , Aminopiridinas/síntesis química , Aminopiridinas/toxicidad , Sitios de Unión , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Mutación , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/toxicidad , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-ret/genética , Urea/análogos & derivados , Urea/síntesis química , Urea/farmacologíaRESUMEN
1,4,8-Trimethylfuro[2,3-h]quinolin-2(1H)-one (compound 5a) is the most interesting derivative among some new furoquinolinones prepared with the aim of moderating the strong toxic effects of 1,4,6,8-tetramethyl derivative (FQ), a powerful potential drug for photomedicine. Compound 5a showed a photobiological activity lower than FQ, but considerable higher than 8-MOP, the furocoumarin used in clinical photomedicine; contrary to classic furocoumarins, 5a induced a strong inhibition of protein synthesis in mammalian cells. Genotoxicity and skin erythema induction, the main side effects of both FQ and 8-MOP photosensitization, are virtually absent with 5a. This behavior seems to be connected to its particular reaction mechanism: differently from furocoumarin derivatives, 5a induced low levels of DNA-protein and no inter-strands cross-links, but formed covalent RNA-protein linkages, lesions not observed with known furocoumarins. Moreover, compound 5a generated reactive oxygen species to a considerable extent. For these features, compound 5a appears to be a new photosensitizing agent whose special activity deserves to be deeply investigated.