Discovery of a small-molecule pBcl-2 inhibitor that overcomes pBcl-2-mediated resistance to apoptosis.
Chembiochem
; 16(5): 757-65, 2015 Mar 23.
Article
em En
| MEDLINE
| ID: mdl-25711460
ABSTRACT
Although the role of Bcl-2 phosphorylation is still under debate, it has been identified in a resistance mechanism to BH3 mimetics, for example ABT-737 and S1. We identified an S1 analogue, S1-16, as a small-molecule inhibitor of pBcl-2. S1-16 efficiently kills EEE-Bcl-2 (a T69E, S70E, and S87E mutant mimicking phosphorylation)-expressing HL-60 cells and high endogenously expressing pBcl-2 cells, by disrupting EEE-Bcl-2 or native pBcl-2 interactions with Bax and Bak, followed by apoptosis. In vitro binding assays showed that S1-16 binds to the BH3 binding groove of EEE-Bcl-2 (Kd =0.38 µM by ITC; IC50 =0.16 µM by ELISA), as well as nonphosphorylated Bcl-2 (npBcl-2; Kd =0.38 µM; IC50 =0.12 µM). However, ABT-737 and S1 had much weaker affinities to EEE-Bcl-2 (IC50 =1.43 and >10 µM, respectively), compared with npBcl-2 (IC50 =0.011 and 0.74 µM, respectively). The allosteric effect on BH3 binding groove by Bcl-2 phosphorylation in the loop region was illustrated for the first time.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Apoptose
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Proteínas Proto-Oncogênicas c-bcl-2
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Bibliotecas de Moléculas Pequenas
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Descoberta de Drogas
Limite:
Animals
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Humans
Idioma:
En
Revista:
Chembiochem
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2015
Tipo de documento:
Article