Peyressatre Marion, Prével Camille, Pellerano Morgan, Morris May C
Institut des Biomolécules Max Mousseron, IBMM-CNRS-UMR5247, 15 Av. Charles Flahault, 34093 Montpellier, France.
Cancers (Basel). 2015 Jan 23;7(1):179-237. doi: 10.3390/cancers7010179.
Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation of cyclins or CDK, contributes to proliferation of cancer cells, and aberrant activity of these kinases has been reported in a wide variety of human cancers. These kinases therefore constitute biomarkers of proliferation and attractive pharmacological targets for development of anticancer therapeutics. The structural features of several of these kinases have been elucidated and their molecular mechanisms of regulation characterized in depth, providing clues for development of drugs and inhibitors to disrupt their function. However, like most other kinases, they constitute a challenging class of therapeutic targets due to their highly conserved structural features and ATP-binding pocket. Notwithstanding, several classes of inhibitors have been discovered from natural sources, and small molecule derivatives have been synthesized through rational, structure-guided approaches or identified in high throughput screens. The larger part of these inhibitors target ATP pockets, but a growing number of peptides targeting protein/protein interfaces are being proposed, and a small number of compounds targeting allosteric sites have been reported.
细胞周期蛋白依赖性激酶（CDK/细胞周期蛋白）构成了一个异二聚体激酶家族，在细胞周期进程、转录以及包括神经元分化和代谢在内的其他主要生物学过程的调控中发挥着核心作用。由于细胞周期蛋白或CDK的扩增、过表达或突变，这些激酶的组成性或失调性过度活跃会导致癌细胞增殖，并且在多种人类癌症中都报道了这些激酶的异常活性。因此，这些激酶构成了增殖的生物标志物以及抗癌治疗药物开发中具有吸引力的药理学靶点。其中几种激酶的结构特征已被阐明，其调控的分子机制也得到了深入研究，这为开发破坏其功能的药物和抑制剂提供了线索。然而，与大多数其他激酶一样，由于它们高度保守的结构特征和ATP结合口袋，它们构成了一类具有挑战性的治疗靶点。尽管如此，已经从天然来源发现了几类抑制剂，并通过合理的、基于结构导向的方法合成了小分子衍生物，或者在高通量筛选中进行了鉴定。这些抑制剂中大部分靶向ATP口袋，但越来越多的靶向蛋白质/蛋白质界面的肽正在被提出，并且已经报道了少数靶向别构位点的化合物。
