RESUMEN
Aberrant activations of Fms-like tyrosine receptor kinase (FLT) 3 are implicated in the pathogenesis of 20% to 30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G-749 yielded complete tumor regression and increased life span in animal models. Thus, G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridonas/uso terapéutico , Pirimidinas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Humanos , Células K562 , Ratones , Proteínas Mutantes/fisiología , Mutación Missense , Estructura Terciaria de Proteína/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/química , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38.
Asunto(s)
Inhibidores de Integrasa VIH/metabolismo , Inhibidores de Integrasa VIH/farmacología , VIH-1/enzimología , Microsomas Hepáticos/metabolismo , Quinolinas/metabolismo , Quinolinas/farmacología , Animales , Perros , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacocinética , Haplorrinos , Humanos , Naftiridinas/química , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Naftiridinas/farmacología , Quinolinas/química , Quinolinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A new series of 1,2,4-triazoles was synthesized and tested against several NNRTI-resistant HIV-1 isolates. Several of these compounds exhibited potent antiviral activities against efavirenz- and nevirapine-resistant viruses, containing K103N and/or Y181C mutations or Y188L mutation. Triazoles were first synthesized from commercially available substituted phenylthiosemicarbazides, then from isothiocyanates, and later by condensing the desired substituted anilines with thiosemicarbazones.