Discovery of potent small molecule ubiquitin-specific protease 10 inhibitors with anti-hepatocellular carcinoma activity through regulating YAP expression.
Eur J Med Chem
; 272: 116468, 2024 Jun 05.
Article
em En
| MEDLINE
| ID: mdl-38718626
ABSTRACT
High expression of ubiquitin-specific protease 10 (USP10) promote the proliferation of hepatocellular carcinoma (HCC), thus the development of USP10 inhibitors holds promise as a novel therapeutic approach for HCC treatment. However, the development of selective USP10 inhibitor is still limited. In this study, we developed a novel USP10 inhibitor for investigating the feasibility of targeting USP10 for the treatment of HCC. Due to high USP10 inhibition potency and prominent selectivity, compound D1 bearing quinolin-4(1H)-one scaffold was identified as a lead compound. Subsequent research revealed that D1 significantly inhibits cell proliferation and clone formation in HCC cells. Mechanistic insights indicated that D1 targets the ubiquitin pathway, facilitating the degradation of YAP (Yes-associated protein), thereby triggering the downregulation of p53 and its downstream protein p21. Ultimately, this cascade leads to S-phase arrest in HCC cells, followed by cell apoptosis. Collectively, our findings highlight D1 as a promising starting point for USP10-positive HCC treatment, underscoring its potential as a vital tool for unraveling the functional intricacies of USP10.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Carcinoma Hepatocelular
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Ubiquitina Tiolesterase
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Proteínas Adaptadoras de Transdução de Sinal
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Proliferação de Células
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Descoberta de Drogas
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Proteínas de Sinalização YAP
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Neoplasias Hepáticas
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China