BCL-2家族蛋白治疗靶点的新维度。
New dimension in therapeutic targeting of BCL-2 family proteins.
作者信息
Besbes Samaher, Mirshahi Massoud, Pocard Marc, Billard Christian
机构信息
INSERM U 965, Hôpital Lariboisière, Paris, France.
Université Paris Diderot, UMR S965, Paris, France.
出版信息
Oncotarget. 2015 May 30;6(15):12862-71. doi: 10.18632/oncotarget.3868.
Abstract
Proteins of the BCL-2 family control the mitochondrial pathway of apoptosis. Targeting these proteins proves to be an attractive strategy for anticancer therapy. The biological context is based on the fact that BH3-only members of the family are specific antagonists of prosurvival members. This prompted the identification of "BH3 mimetic" compounds. These small peptides or organic molecules indeed mimic the BH3 domain of BH3-only proteins: by selectively binding and antagonizing prosurvival proteins, they can induce apoptosis in malignant cells. Some small-molecule inhibitors of prosurvival proteins have already entered clinical trials in cancer patients and two of them have shown significant therapeutic effects. The latest developments in the field of targeting BCL-2 family proteins highlight several new antagonists of prosurvival proteins as well as direct activators of proapoptotic proteins. These compounds open up novel prospects for the development of BH3 mimetic anticancer drugs.
摘要
BCL-2家族蛋白控制细胞凋亡的线粒体途径。事实证明，靶向这些蛋白是一种颇具吸引力的抗癌治疗策略。其生物学背景基于该家族中仅含BH3结构域的成员是促生存成员的特异性拮抗剂这一事实。这促使人们鉴定出“BH3模拟物”化合物。这些小肽或有机分子确实模拟了仅含BH3结构域蛋白的BH3结构域：通过选择性结合并拮抗促生存蛋白，它们可诱导恶性细胞凋亡。一些促生存蛋白的小分子抑制剂已进入癌症患者的临床试验，其中两种已显示出显著的治疗效果。靶向BCL-2家族蛋白领域的最新进展突出了几种促生存蛋白的新拮抗剂以及促凋亡蛋白的直接激活剂。这些化合物为开发BH3模拟抗癌药物开辟了新前景。
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