Structure-based discovery of a new class of Bcl-xL antagonists
Structure-based discovery of a new class of Bcl-xL antagonists
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DOI：
10.1016/j.bioorg.2007.03.001
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发表时间：
2007-08-01
影响因子：
5.1
通讯作者：
Pellecchia, Maurizio
中科院分区：
文献类型：
--
作者：
Rega, Michele F.;Leone, Marilisa;Pellecchia, Maurizio
细胞凋亡或程序性细胞死亡在正常组织稳态中起关键作用，确保细胞产生和细胞损失之间的适当平衡。抗凋亡Bcl-2家族蛋白是凋亡途径的中心调节因子，并且由于其赋予肿瘤对化疗或放疗的抗性的能力，最近已被验证为癌症药物发现的靶点。由于促凋亡和抗凋亡成员之间的关键相互作用通过位于蛋白质表面上的保守区域发生，抑制Bcl-2蛋白的抗死亡活性的可行方法是设计占据该空腔的小分子抑制剂。在这里，我们描述了一种基于结构的方法，该方法鉴定了四种针对Bcl-2家族蛋白BCI-x（L）表面疏水沟的小分子抑制剂。化合物在许多测定中表征，包括使用N-15-标记的蛋白质的体外结合、置换DELFIA测定和使用人癌细胞的基于细胞的活力测定。(c)2007年爱思唯尔公司All rights reserved.
Apoptosis, or programmed cell death, plays a key role in normal tissue homeostasis ensuring a proper balance between cell production and cell loss. Anti-apoptotic Bcl-2-family proteins are central regulators of the apoptotic pathway and due to their ability to confer tumor resistance to chemotherapy or radiation, have been recently validated as targets for cancer drug discovery. Since the crucial interaction between pro- and anti-apoptotic members occurs via a conserved region located on the surface of the protein, a viable way to inhibit the anti-death activity of Bcl-2 proteins is to design small molecule inhibitors that occupy this cavity. Here, we describe a structure-based approach that led to the identification of four small molecule inhibitors directed at the hydrophobic groove on the surface of the Bcl-2 family protein BCI-x(L). The compounds were characterized in a number of assays including in vitro binding using N-15-labeled protein, a displacement DELFIA assay, and a cell-based viability assay with human cancer cells. (c) 2007 Elsevier Inc. All rights reserved.