Novel small-molecule inhibitors of Bcl-XL to treat lung cancer.
Novel small-molecule inhibitors of Bcl-XL to treat lung cancer.
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DOI：
10.1158/0008-5472.can-12-2272
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发表时间：
2013-09-01
期刊：
影响因子：
11.2
通讯作者：
Deng X
中科院分区：
文献类型：
--
作者：
Park D;Magis AT;Li R;Owonikoko TK;Sica GL;Sun SY;Ramalingam SS;Khuri FR;Curran WJ;Deng X
Bcl-XL是Bcl-2家族中的主要抗凋亡蛋白，其过表达在人肺癌细胞中比Bcl-2的过表达更广泛地观察到，这表明Bcl-XL更具有生物学相关性，因此是肺癌的更好的治疗靶点。在这里，我们使用UCSF DOCK 6.1程序套件和NCI化学文库数据库筛选了选择性靶向Bcl-XL的BH 3结构域（aa 90-98）结合口袋的小分子。我们鉴定了两种新的Bcl-XL抑制剂（BXI-61和BXI-72），与正常人支气管上皮细胞相比，它们对肺癌细胞表现出选择性毒性。荧光偏振分析表明，BXI-61和BXI-72在体外与Bcl-XL蛋白结合，而与Bcl-2、Bcl-w、Bfl-1/A1和Mcl-1蛋白结合不明显。用BXI-72处理细胞导致Bcl-XL/巴克或Bcl-XL/Bax相互作用的破坏、巴克的寡聚化和细胞色素c从线粒体释放。重要的是，BXI-61和BXI-72对人肺癌的疗效比ABT-737更强，但体内血小板减少程度较低。BXI-72克服了肺癌的获得性放射抗性。基于我们的研究结果，BXI（s）作为一类新的抗癌药物的开发是必要的，代表了一种改善肺癌结局的新策略。
Bcl-XL is a major anti-apoptotic protein in the Bcl-2 family whose overexpression is more widely observed in human lung cancer cells than that of Bcl-2, suggesting that Bcl-XL is more biologically relevant and therefore a better therapeutic target for lung cancer. Here, we screened small molecules that selectively target the BH3 domain (aa 90–98) binding pocket of Bcl-XL using the UCSF DOCK 6.1 program suite and the NCI chemical library database. We identified two new Bcl-XL inhibitors (BXI-61 and BXI-72) that exhibit selective toxicity against lung cancer cells compared with normal human bronchial epithelial cells. Fluorescence polarization assay reveals that BXI-61 and BXI-72 preferentially bind to Bcl-XL protein but not Bcl2, Bcl-w, Bfl-1/A1 or Mcl-1 in vitro with high binding affinities. Treatment of cells with BXI-72 results in disruption of Bcl-XL/Bak or Bcl-XL/Bax interaction, oligomerization of Bak and cytochrome c release from mitochondria. Importantly, BXI-61 and BXI-72 exhibit more potent efficacy against human lung cancer than ABT-737 but less degree in platelet reduction in vivo. BXI-72 overcomes acquired radioresistance of lung cancer. Based on our findings, the development of BXI(s) as a new class of anticancer agents is warranted and represents a novel strategy for improving lung cancer outcome.