Discovery of a new selective inhibitor of A Disintegrin And Metalloprotease 10 (ADAM-10) able to reduce the shedding of NKG2D ligands in Hodgkin's lymphoma cell models.
Eur J Med Chem
; 111: 193-201, 2016 Mar 23.
Article
em En
| MEDLINE
| ID: mdl-26871660
ABSTRACT
Hodgkin's lymphoma (HL) is the most common malignant lymphoma in young adults in the western world. This disease is characterized by an overexpression of ADAM-10 with increased release of NKG2D ligands, involved in an impaired immune response against tumor cells. We designed and synthesized two new ADAM-10 selective inhibitors, 2 and 3 based on previously published ADAM-17 selective inhibitor 1. The most promising compound was the thiazolidine derivative 3, with nanomolar activity for ADAM-10, high selectivity over ADAM-17 and MMPs and good efficacy in reducing the shedding of NKG2D ligands (MIC-B and ULBP3) in three different HL cell lines at non-toxic doses. Molecular modeling studies were used to drive the design and X-ray crystallography studies were carried out to explain the selectivity of 3 for ADAM-10 over MMPs.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Hodgkin
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Inibidores Enzimáticos
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Proteínas ADAM
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Secretases da Proteína Precursora do Amiloide
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Subfamília K de Receptores Semelhantes a Lectina de Células NK
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Descoberta de Drogas
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Proteínas de Membrana
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article