Studies leading to potent, dual inhibitors of bcl-2 and Bcl-xL
Studies leading to potent, dual inhibitors of bcl-2 and Bcl-xL
复制标题
DOI：
10.1021/jm061152t
复制
发表时间：
2007-02-22
影响因子：
7.3
通讯作者：
Elmore, Steven W.
中科院分区：
文献类型：
--
作者：
Bruncko, Milan;Oost, Thorsten K.;Elmore, Steven W.
抗细胞凋亡蛋白Bcl2和Bclxl的过度表达为癌细胞获得生存优势和对传统化疗产生耐药性提供了一种常见的机制。抑制这些生存蛋白是癌症治疗的一个有吸引力的策略。我们最近发现了一种选择性的Bclxl拮抗剂，它可以增强化疗和放射治疗的抗肿瘤活性。在这里，我们描述了利用结构导向设计来开发这些蛋白质表面的深疏水结合口袋来开发第一个二元的、亚纳米分子的Bclxl和Bcl2的抑制剂。本研究最终鉴定了2，其在Bcl2和BclXL依赖细胞中的EC50值分别为8 nM和30 nM。化合物2对高表达Bcl-2的人滤泡性淋巴瘤细胞株显示出单药疗效，在小鼠淋巴瘤异种移植模型中显示出单独给药和与依托泊苷联合给药的效果。
Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.