Discovery of pyrido[3,4-b]indol-1-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors.
Bioorg Chem
; 119: 105541, 2022 02.
Article
em En
| MEDLINE
| ID: mdl-34910982
ABSTRACT
Bruton's tyrosine kinase (BTK) is an attractive target for the treatment of malignancy and inflammatory/autoimmune diseases. Most of the covalent BTK inhibitors would induce off-target side effects and drug resistance. To improve the drug safety of BTK inhibitors, non-covalent inhibitors have attracted more and more attention. We designed a series of novel pyrido[3,4-b]indol-1-one derivatives (N-A and N-B) via scaffold hopping from CGI-1746. The structure-activity relationship (SAR) of the newly-synthesized compounds was explored. The results showed that compounds 12 and 18 exhibited potent enzymatic potency against BTK with IC50 values of 0.22 µM and 0.19 µM, respectively. In lymphoma cell lines U-937 cells and Ramos cells, compounds 12 and 18 displayed comparative antiproliferative activity with Ibrutinib. Moreover, compound 12 induced G1-phase cell cycle arrest and apoptosis in U-937 cells. And it could effectively inhibit tumor growth in U-937 xenograft mouse model (TGI = 41.90% at 50 mg/kg). In all, the new pyrido[3,4-b]indol-1-one derivatives have the antitumor potency by BTK inhibition and were worthy of further exploration.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
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Descoberta de Drogas
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Tirosina Quinase da Agamaglobulinemia
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Indóis
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China