Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL

被引：499

作者：

Degterev, A

Lugovskoy, A

Cardone, M

Mulley, B

Wagner, G

Mitchison, T

Yuan, JY

机构：

[1] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Inst Chem & Cell Biol, Boston, MA 02115 USA

[3] Harvard Univ, Comm Higher Degrees Biophys, Cambridge, MA 02138 USA

[4] Harvard Univ, Sch Med, Dept Mol Pharmacol & Biochem, Boston, MA 02115 USA

[5] MIT, Dept Biol, Cambridge, MA 02138 USA

来源：

NATURE CELL BIOLOGY | 2001年 / 3卷 / 02期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1038/35055085

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

To study the role of the BH3 domain in mediating pro-apoptotic and anti-apoptotic activities of Bcl-2 family members, we identified a series of novel small molecules (BH3Is) that inhibit the binding of the Bak BH3 peptide to Bcl-x(L). NMR analyses revealed that BH3Is target the BH3-binding pocket of Bcl-x(L). Inhibitors specifically block the BH3-domain-mediated heterodimerization between Bcl-2 family members in vitro and in vivo and induce apoptosis. Our results indicate that BH3-dependent heterodimerization is the key function of anti-apoptotic Bcl-2 family members and is required for the maintenance of cellular homeostasis.

引用

页码：173 / 182

页数：10

共 49 条

[41] Synthesis and applications of small molecule libraries [J].