Design, synthesis, and biological evaluation of pyrido[3,2-d]pyrimidine derivatives as novel ATR inhibitors.
Bioorg Chem
; 136: 106535, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-37086581
ABSTRACT
Targeting ataxia telangiectasia mutated and Rad3-related (ATR) kinase is being pursued as a new therapeutic strategy for the treatment of advanced solid tumor with specific DNA damage response deficiency. Herein, we report a series of pyrido[3,2-d]pyrimidine derivatives with potent ATR inhibitory activity through structure-based drug design. Among them, the representative compound 10q exhibited excellent potency against ATR in both biochemical and cellular assays. More importantly, 10q exhibited good liver microsomes stability in different species and also showed moderate inhibitory activity against HT-29 cells in combination treatment with the ATM inhibitor AZD1390. Thus, this work provides a promising lead compound against ATR for further study.
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Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Inibidores de Proteínas Quinases
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article