Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity.
J Med Chem
; 67(18): 16480-16504, 2024 Sep 26.
Article
em En
| MEDLINE
| ID: mdl-39264152
ABSTRACT
Epigenetic therapies have emerged as a key paradigm for treating malignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by fusing the key pharmacophores from DNMT1 inhibitors (DNMT1i) and HDAC inhibitors (HDACi). Among them, compound (R)-23a demonstrated significant DNMT1 and HDAC inhibition both in vitro and in cells and largely phenocopied the synergistic effects of combined DNMT1i and HDACi in reactivating epigenetically silenced tumor suppressor genes (TSGs). This translated into a profound tumor growth inhibition (TGI = 98%) of (R)-23a in an MV-4-11 xenograft model, while displaying improved tolerability compared with single agent combination. Moreover, in a syngeneic MC38 mouse colorectal tumor model, (R)-23a outperformed the combinatory treatment in reshaping the tumor immune microenvironment and inducing tumor regression. Collectively, the novel DNMT1/HDAC dual inhibitor (R)-23a effectively reverses the cancer-specific epigenetic abnormalities and holds great potential for further development into cancer therapeutic agents.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Histona Desacetilases
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DNA (Citosina-5-)-Metiltransferase 1
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Antineoplásicos
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
Estados Unidos