Discovery of DB18, a potent inhibitor of CLK kinases with a high selectivity against DYRK1A kinase.
Bioorg Med Chem
; 31: 115962, 2021 02 01.
Article
em En
| MEDLINE
| ID: mdl-33422908
ABSTRACT
We describe in this paper the synthesis of a novel series of anilino-2-quinazoline derivatives. These compounds have been screened against a panel of eight mammalian kinases and in parallel they were tested for cytotoxicity on a representative panel of seven cancer cell lines. One of them (DB18) has been found to be a very potent inhibitor of human "CDC2-like kinases" CLK1, CLK2 and CLK4, with IC50 values in the 10-30 nM range. Interestingly, this molecule is inactive at 100 µM on the closely related "dual-specificity tyrosine-regulated kinase 1A" (DYRK1A). Extensive molecular simulation studies have been performed on the relevant kinases to explain the strong affinity of this molecule on CLKs, as well as its selectivity against DYRK1A.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Tirosina Quinases
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Proteínas Serina-Treonina Quinases
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Inibidores de Proteínas Quinases
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Descoberta de Drogas
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Índia