Discovery of 7H-pyrrolo[2,3-d]pyrimidine derivatives as selective covalent irreversible inhibitors of interleukin-2-inducible T-cell kinase (Itk).
Eur J Med Chem
; 173: 167-183, 2019 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-30999237
ABSTRACT
Interleukin-2-inducible T-cell kinase (Itk) plays an important role in multiple signal transduction pathways in T and mast cells, and is a potential drug target for treating inflammatory diseases, autoimmune diseases, and T cell leukemia/lymphoma. Herein, we describe the discovery of a series of covalent Itk inhibitors based on the 7H-pyrrolo[2,3-d]pyrimidine scaffold. Placing an appropriate substitution group at a hydration site of the ATP binding pocket of Itk and using a saturated heterocyclic ring as a linker to the reactive group were crucial for selectivity. The optimized compound 9 showed potent activity against Itk, excellent selectivity for Itk over Btk and other structurally related kinases, inhibition of phospholipase C-γ1 (PLC-γ1) phosphorylation in cells, and anti-proliferative effects against multiple T leukemia/lymphoma cell lines. Compound 9 can serve as a valuable compound for further determination of functions of Itk.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Proteínas Tirosina Quinases
/
Inibidores de Proteínas Quinases
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Descoberta de Drogas
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2019
Tipo de documento:
Article