Design, synthesis and biological evaluation of a new class of 7H-pyrrolo[2,3-d]pyrimidine derivatives as Mps1 inhibitors for the treatment of breast cancer.
Eur J Med Chem
; 245(Pt 1): 114887, 2023 Jan 05.
Article
em En
| MEDLINE
| ID: mdl-36370549
ABSTRACT
Monopolar spindle kinase 1 (Mps1), a core component of the spindle assembly checkpoint (SAC), plays a crucial role in the transition of cells from mid-to late mitosis. As an attractive therapeutic target, inhibition of Mps1 induces cell cycle arrest and apoptosis in a variety of tumors, including breast cancer. However, early clinical development of Mps1 inhibitors remains unsatisfactory. Here, we designed and synthesized a new class of Mps1 inhibitors with 7H-pyrrolo[2,3-d]pyrimidine structure using a scaffold hopping approach. Structure-activity relationship (SAR) revealed that 12 is a potent Mps1 inhibitor (IC50 = 29 nM), which inhibited phosphorylation of Mps1 in vitro and in vivo. Treatment with 12 not only impeded proliferation of breast cancer cell lines, but also induced cell cycle arrest and apoptosis of MCF-7 and 4T1 cells. 12 suppressed tumor growth in vivo, and no obvious toxicities were observed. These results demonstrated the potential of Mps1 inhibitor 12 for the treatment of breast cancer.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Neoplasias da Mama
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Proteínas Serina-Treonina Quinases
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Inibidores de Proteínas Quinases
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Antineoplásicos
Limite:
Female
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China