Logical design of an anti-cancer agent targeting the plant homeodomain in Pygopus2.
Cancer Sci
; 107(9): 1321-8, 2016 Sep.
Article
em En
| MEDLINE
| ID: mdl-27324116
ABSTRACT
Pygopus2 (Pygo2) is a component of the Wnt signaling pathway, which is required for ß-catenin mediated transcription. Plant homeodomain (PHD) finger in Pygo2 intercalates the methylated histone 3 (H3K4me) tail and HD1 domain of BCL9 that binds to ß-catenin. Thus, PHD finger may be a potential target for the logical design of an anti-cancer drug. Here, we found that Spiro[2H-naphthol[1,2-b]pyran-2,4'-piperidine]-1'ethanol,3,4-dihydro-4-hydroxy-α-(6-methyl-1H-indol-3-yl)) termed JBC117 interacts with D339, A348, R356, V376 and A378 in PHD corresponding to the binding sites with H3K4me and/or HD1, and has strong anti-cancer effects. For colon (HCT116) and lung (A549) cancer cell lines, IC50 values were 2.6 ± 0.16 and 3.3 ± 0.14 µM, respectively, while 33.80 ± 0.15 µM for the normal human fibroblast cells. JBC117 potently antagonized the cellular effects of ß-catenin-dependent activity and also inhibited the migration and invasion of cancer cells. In vivo studies showed that the survival time of mice was significantly prolonged by the subcutaneous injection of JBC117 (10 mg/kg/day). In conclusion, JBC117 is a novel anti-cancer lead compound targeting the PHD finger of Pygo2 and has a therapeutic effect against colon and lung cancer.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
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Prevencao_e_fatores_de_risco
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Alcoolismo
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Tipos_de_cancer
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Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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Proteínas de Homeodomínio
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Peptídeos e Proteínas de Sinalização Intracelular
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Domínios e Motivos de Interação entre Proteínas
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Antineoplásicos
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Cancer Sci
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Japão