RESUMO
Activating mutations of FMS-like tyrosine kinaseâ 3 (FLT3) are present in â¼30 % of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Point mutations in the tyrosine kinase domain (TKD) are observed as primary mutations or are acquired as secondary mutations in FLT3 with internal tandem duplications (ITDs) after treatment with tyrosine kinase inhibitors (TKIs). Although dozens of potent inhibitors against FLT3 ITD have been reported, activating TKD point mutations, especially at residues F691 and D835, remain the leading cause for therapy resistance, highlighting the consistent need for new potent inhibitors. Herein we report the identification and characterization of novel quinoxaline-based FLT3 inhibitors. We used the pharmacophore features of diverse known inhibitors as a starting point for a new optimization algorithm for typeâ II TKIs, starting from an in silico library pharmacophore search and induced-fit docking in the known FLT3 structure. This led to the design of a set of diverse quinoxalinebisarylureas, which were profiled in an FLT3 kinase activity assay. The most promising compounds were further evaluated in a zebrafish embryo phenotype assay.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Desenho de Fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Quinoxalinas/síntese química , Peixe-Zebra , Tirosina Quinase 3 Semelhante a fms/química , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
Modulation of γ-secretase activity holds potential for the treatment of Alzheimer's disease. Most NSAID-derived γ-secretase modulators feature a carboxylic acid, which may impair blood-brain barrier permeation. The structure activity relationship of 33 carbazoles featuring diverse carboxylic acid isosteres or metabolic precursors thereof was established in a cellular amyloid secretion assay. The modulatory activity was observed for acidic moieties and metabolically labile esters only, which supports our hypothesis of an acid-lysine interaction to be relevant for this type of γ-secretase modulators.