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Int J Mol Sci ; 23(24)2022 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-36555810

RESUMEN

Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid the reduced efficacy of therapy have been explored, including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for the survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here the structure-activity relationship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase, and the isopropyl group at position 7 substantially increased the selectivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piperazin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses, including the suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo.


Asunto(s)
Leucemia Mieloide Aguda , Ratones , Humanos , Animales , Línea Celular Tumoral , Leucemia Mieloide Aguda/tratamiento farmacológico , Relación Estructura-Actividad , Inhibidores de Proteínas Quinasas/uso terapéutico , Fosforilación , Tirosina Quinasa 3 Similar a fms , Proliferación Celular , Apoptosis , Mutación
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