Discovery of highly potent PARP7 inhibitors for cancer immunotherapy.
Bioorg Chem
; 148: 107469, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38781669
ABSTRACT
PARP7 has been proven to play an important role in immunity. Substantial upregulation of PARP7 is observed in numerous cancerous cell types, consequently resulting in the inhibition of type â
interferon signaling pathways. Therefore, inhibiting the activity of PARP7 can enhance type â
interferon signaling to exert an anti-tumor immune response. In this study, we reported the identification of a newly found PARP7 inhibitor (XLY-1) with higher inhibitory activity (IC50 = 0.6 nM) than that of RBN-2397 (IC50 = 6.0 nM). Additionally, XYL-1 displayed weak inhibitory activity on PARP1 (IC50 > 1.0 µM). Mechanism studies showed that XYL-1 could enhance the type â
interferon signaling in vitro. Pharmacodynamic experiments showed that 50 mg/kg XYL-1 could significantly inhibit tumor growth (TGI 76.5 %) and related experiments showed that XYL-1 could restore type â
interferon signaling and promote T cell infiltration in tumor tissues. Taken together, XYL-1 shows promise as a potential candidate for developing cancer immunotherapy agents.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ensaios de Seleção de Medicamentos Antitumorais
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Proliferação de Células
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Relação Dose-Resposta a Droga
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Descoberta de Drogas
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Inibidores de Poli(ADP-Ribose) Polimerases
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Imunoterapia
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Antineoplásicos
Limite:
Animals
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Humans
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China