Design, synthesis, and biological evaluation of 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as novel dual-PLK1/BRD4 inhibitors.
Eur J Med Chem
; 191: 112152, 2020 Apr 01.
Article
en En
| MEDLINE
| ID: mdl-32088495
ABSTRACT
Protein kinase inhibitors and epigenetic regulatory molecules are two main kinds of anticancer drugs developed in recent years. Both kinds of drugs harbor their own advantages and disadvantages in the treatment of cancer, and the development of small molecules which could target at kinases and epigenetic targets simultaneously can avoid the defects of drugs which only targets at kinases or epigenetic proteins. In this study, a series of 4,5-dihydro-[1,2,4]triazolo [4,3-f]pteridine derivatives were designed and synthesized based on the structure of PLK1 inhibitor BI-2536. Subsequent targets affinity screen and antiproliferative activity test led to the discovery of the most potent dual PLK1/BRD4 inhibitor 9b with good potency for both PLK1 (IC50 = 22 nM) and BRD4 (IC50 = 109 nM) as well as favorable antiproliferative activity against a panel of cancer cell lines. 9b could induce cell cycle arrest and apoptosis in acute myeloid leukemia cell line MV 4-11 in a concentration dependent manner. It could also downregulate the transcription of several proliferation-related oncogenes, including c-MYC, MYCN and BCL-2. Finally, in a MV4-11 mouse xenograft model, 9b exhibited favorable in vivo antitumor activity with 66% tumor growth inhibition (TGI) at a dose of 60 mg/kg while without obvious toxicity. This study thus provided us a start point for the development of new dual PLK1/BRD4 inhibitors as anticancer agents.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pteridinas
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Factores de Transcripción
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Triazoles
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Diseño de Fármacos
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Proteínas Proto-Oncogénicas
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Proteínas Serina-Treonina Quinasas
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Proteínas de Ciclo Celular
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Inhibidores de Proteínas Quinasas
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Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Eur J Med Chem
Año:
2020
Tipo del documento:
Article