Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML.
Eur J Med Chem
; 275: 116539, 2024 Sep 05.
Article
em En
| MEDLINE
| ID: mdl-38878515
ABSTRACT
AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells. Compound C3, featuring a 4-methylpiperidine ring linker, effectively degraded CDK2 with a DC50 value of 18.73 ± 10.78 nM, and stimulated 72.77 ± 3.51 % cell differentiation at 6.25 nM in HL-60 cells. Moreover, C3 exhibited potent anti-proliferative activity against various AML cell types. Degradation selectivity analysis indicated that C3 could be endowed with efficient degradation of CDK2/4/6/9 and FLT3, especially FLT3-ITD in MV4-11 cells. These findings propose that C3 combined targeting CDK2/4/6/9 and FLT3 with enhanced differentiation and proliferation inhibition, which holds promise as a potential treatment for AML.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
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Quinases Ciclina-Dependentes
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Inibidores de Proteínas Quinases
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Tirosina Quinase 3 Semelhante a fms
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Descoberta de Drogas
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Proteólise
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Quimera de Direcionamento de Proteólise
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2024
Tipo de documento:
Article