Design, synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel potent CDK7 inhibitors.
Bioorg Chem
; 148: 107456, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38761706
ABSTRACT
The targeting of cyclin-dependent kinase 7 (CDK7) has become a highly desirable therapeutic approach in the field of oncology due to its dual role in regulating essential biological processes, encompassing cell cycle progression and transcriptional control. We have previously identified a highly selective thieno[3,2-d]pyrimidine-based CDK7 inhibitor with demonstrated efficacy and safety in animal model. In this study, we sought to optimize the thieno[3,2-d]pyrimidine core to discover a novel series of CDK7 inhibitors with improved potency and pharmacokinetic (PK) properties. Through extensive structure-activity relationship (SAR) studies, compound 20 has emerged as the lead candidate due to its potent inhibitory activity against CDK7 and remarkable efficacy on MDA-MB-453 cells, a representative triple negative breast cancer (TNBC) cell line. Furthermore, 20 has demonstrated favorable oral bioavailability and exhibited highly desirable pharmacokinetic (PK) properties, making it a promising lead candidate for further structural optimization.
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Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Desenho de Fármacos
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Quinases Ciclina-Dependentes
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Inibidores de Proteínas Quinases
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Quinase Ativadora de Quinase Dependente de Ciclina
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Antineoplásicos
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article