Mariaule Gaëlle, Belmont Philippe
Institut Curie, UMR CNRS 176, 26 rue d'Ulm, Paris 75005, France.
Molecules. 2014 Sep 11;19(9):14366-82. doi: 10.3390/molecules190914366.
In the early 2000s, the anticancer drug imatinib (Glivec®) appeared on the market, exhibiting a new mode of action by selective kinase inhibition. Consequently, kinases became a validated therapeutic target, paving the way for further developments. Although these kinases have been thoroughly studied, none of the compounds commercialized since then target cyclin-dependent kinases (CDKs). Following a recent and detailed review on the subject by Galons et al., we concentrate our attention on an updated list of compounds under clinical evaluation (phase I/II/III) and discuss their mode of action as ATP-competitive inhibitors. CDK inhibition profiles and clinical development stages are reported for the 14 compounds under clinical evaluation. Also, tentative progress for forthcoming potential ATP non-competitive inhibitors and allosteric inhibitors are briefly described, along with their limitations.
21世纪初，抗癌药物伊马替尼（格列卫®）上市，通过选择性激酶抑制展现出一种新的作用模式。因此，激酶成为了一个经过验证的治疗靶点，为进一步的研发铺平了道路。尽管这些激酶已被深入研究，但自那时起商业化的化合物中没有一种靶向细胞周期蛋白依赖性激酶（CDK）。在加隆斯等人最近对该主题进行详细综述之后，我们将注意力集中在一份正在进行临床评估（I/II/III期）的化合物更新列表上，并讨论它们作为ATP竞争性抑制剂的作用模式。报告了14种正在进行临床评估的化合物的CDK抑制谱和临床开发阶段。此外，还简要描述了即将出现的潜在ATP非竞争性抑制剂和变构抑制剂的初步进展及其局限性。
