Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit.
Bioorg Med Chem Lett
; 28(17): 2939-2944, 2018 09 15.
Article
em En
| MEDLINE
| ID: mdl-30122225
ABSTRACT
Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR.
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Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
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Descoberta de Drogas
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Tirosina Quinase da Agamaglobulinemia
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article