Coming full circle: cyclin-dependent kinases as anti-cancer drug targets.
Coming full circle: cyclin-dependent kinases as anti-cancer drug targets.
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DOI：
10.1007/978-90-481-3471-7_1
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发表时间：
2010
影响因子：
--
通讯作者：
R. Fisher
中科院分区：
文献类型：
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作者：
R. Fisher
由于细胞增殖的正常控制在癌症中受到干扰，触发DNA合成和有丝分裂的细胞周期蛋白依赖性蛋白激酶(CDK)已成为小分子抑制的热门靶点，但这是否会是一种有效的抗肿瘤策略仍未定论。关于哺乳动物细胞周期中活跃的多种CDK中的哪一种可能是好的靶点，存在争议，这反映了对于这些不同的CDK到底有什么作用的根本困惑。在经典的观点中，主要基于它们在细胞周期中的激活时间，不同的CDK被专门用于在不同的细胞周期间隔中执行不同的功能。一种修正主义模型已经出现，在这种模型中，细胞分裂所必需的所有功能都可以由一个催化亚单位执行，这是基于细胞的增殖能力和动物的生存能力，当单个CDK通过基因缺失或通过RNA干扰而被去除时。这些情况与CDK被药物抑制的情况完全不同，这一点经常被忽视或淡化。由于最近的研究揭示了密切相关的CDK和CDK特定角色在S阶段的时间控制中动态不同的激活路径，一幅更细微和准确的图景现已浮出水面。CDK能否在癌症中有效靶向的基本问题尚未得到回答，但现在可以在化学遗传模型系统中解决，该模型系统近似于体内真正选择性抑制CDK的情况-仍然是假设的-。
Because the normal control of cell proliferation is disturbed in cancer, the cyclin-dependent kinases (CDKs) that trigger DNA synthesis and mitosis have been popular targets for inhibition with small molecules, but the jury is still out on whether this will be an effective anti-tumor strategy. There is debate about which of the multiple CDKs active during the mammalian cell cycle might be good targets, reflecting fundamental confusion about what, precisely, those different CDKs really do. In the classical view, based largely on their activation timing in cycling cells, different CDKs are specialized to perform discrete functions during distinct cell-cycle intervals. A revisionist model has emerged in which all functions essential to cell division can be performed by a single catalytic subunit, based on the ability of cells to proliferate and animals to survive when individual CDKs are removed by gene deletion or depleted by RNA interference. That those situations in no way resemble ones in which CDKs are inhibited pharmacologically is often overlooked or downplayed. A more nuanced – and accurate – picture is now coming into view, thanks to recent studies that reveal kinetically distinct pathways of activation for closely related CDKs and CDK-specific roles in the temporal control of S phase. The basic question of whether CDKs can be effectively targeted in cancer has yet to be answered but can now be addressed in chemical-genetic model systems that approximate the situation – still hypothetical – of truly selective CDK inhibition in vivo.