3H-Pyrazolo[4,3-f]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo.
J Med Chem
; 64(15): 10981-10996, 2021 08 12.
Article
em En
| MEDLINE
| ID: mdl-34288692
ABSTRACT
The 3H-pyrazolo[4,3-f]quinoline moiety has been recently shown to be a privileged kinase inhibitor core with potent activities against acute myeloid leukemia (AML) cell lines in vitro. Herein, various 3H-pyrazolo[4,3-f]quinoline-containing compounds were rapidly assembled via the Doebner-Povarov multicomponent reaction from the readily available 5-aminoindazole, ketones, and heteroaromatic aldehydes in good yields. The most active compounds potently inhibit the recombinant FLT3 kinase and its mutant forms with nanomolar IC50 values. Docking studies with the FLT3 kinase showed a type I binding mode, where the 3H-pyrazolo group interacts with Cys694 in the hinge region. The compounds blocked the proliferation of AML cell lines harboring oncogenic FLT3-ITD mutations with remarkable IC50 values, which were comparable to the approved FLT3 inhibitor quizartinib. The compounds also inhibited the growth of leukemia in a mouse-disseminated AML model, and hence, the novel 3H-pyrazolo[4,3-f]quinoline-containing kinase inhibitors are potential lead compounds to develop into anticancer agents, especially for kinase-driven cancers.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
/
Inibidores de Proteínas Quinases
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Tirosina Quinase 3 Semelhante a fms
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article