Synthesis and evaluation of novel N1-acylated 5-(4-pyridinyl)indazole derivatives as potent and selective haspin inhibitors.
Bioorg Chem
; 145: 107235, 2024 Apr.
Article
em En
| MEDLINE
| ID: mdl-38447464
ABSTRACT
Protein kinase dysregulation was strongly linked to cancer pathogenesis. Moreover, histone alterations were found to be among the most important post-translational modifications that could contribute to cancer growth and development. In this context, haspin, an atypical serine/threonine kinase, phosphorylates histone H3 at threonine-3 and is notably overexpressed in various common cancer types. Herein, we report novel 5-(4-pyridinyl)indazole derivatives as potent and selective haspin inhibitors. Amide coupling at N1 of the indazole ring with m-hydroxyphenyl acetic acid yielded compound 21 with an IC50 value of 78 nM against haspin. This compound showed a meaningful selectivity over 15 of the most common off-targets, including Clk 1-3 and Dyrk1A, 1B, and 2. The most potent haspin inhibitors 5 and 21 effectively inhibited the growth of the NCI-60 cancer cell lines, further emphasizing the success of our scaffold as a new selective lead for the development of anti-cancer therapeutic agents.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos e Proteínas de Sinalização Intracelular
/
Antineoplásicos
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Egito