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JAK3 inhibitors based on thieno[3,2-d]pyrimidine scaffold: design, synthesis and bioactivity evaluation for the treatment of B-cell lymphoma.
Bioorg Chem ; 95: 103542, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31918398
ABSTRACT
JAK3 is predominantly expressed in hematopoietic cells and has been a promising therapeutic target for the treatment of B-cell lymphoma. In this study, a new class of thieno[3,2-d]pyrimidines harboring acrylamide pharmacophore were synthesized as potent covalent JAK3 inhibitors (IC50 < 10 nM). Among them, 9a and 9 g displayed the strongest inhibitory potency against JAK3 kinase activity, with IC50 values of 1.9 nM and 1.8 nM, respectively. Furthermore, compared with the reference agents, Spebrutinib and Ibrutinib, 9a not only demonstrated enhanced antiproliferative activity against B lymphoma cells, but also showed very weak proliferative inhibition against normal peripheral blood mononuclear cells (PBMCs) at a concentration of 20 µM. Analysis of the mechanism revealed that 9a could induce the obvious apoptosis in B lymphoma cells and prevent JAK3-STAT3 cascade as well as BTK pathway. Taken together, 9a may be served as a potential new JAK3 inhibitor for the treatment of B-cell lymphoma.

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Idioma: Inglês Revista: Bioorg Chem Ano de publicação: 2020 Tipo de documento: Artigo