Discovery of a potent Gilteritinib-based FLT3-PROTAC degrader for the treatment of Acute myeloid leukemia.
Bioorg Chem
; 149: 107477, 2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-38820938
ABSTRACT
Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin-proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Pirazinas
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Ensayos de Selección de Medicamentos Antitumorales
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Leucemia Mieloide Aguda
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Inhibidores de Proteínas Quinasas
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Proliferación Celular
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Relación Dosis-Respuesta a Droga
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Tirosina Quinasa 3 Similar a fms
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Antineoplásicos
Idioma:
En
Revista:
Bioorg Chem
Año:
2024
Tipo del documento:
Article