Meijer Laurent, Raymond Eric
Station Biologique de Roscoff, C.N.R.S., BP 74, 29682 Roscoff Cedex, Bretagne, France.
Acc Chem Res. 2003 Jun;36(6):417-25. doi: 10.1021/ar0201198.
This article reviews the steps that have led us from very fundamental research on the cell division cycle, investigated with the starfish oocyte model, to the identification of drugs now being evaluated against cancer in the clinic. Among protein kinases activated during entry in M phase, the cyclin-dependent kinase CDK1/cyclin B was initially identified as a universal M-phase promoting factor. It was then used as a screening target to identify pharmacological inhibitors. The first inhibitors to be discovered were 6-dimethylaminopurine and isopentenyladenine, from which more potent and selective inhibitors were optimized (olomoucine, roscovitine, and purvalanols). All were cocrystallized with CDK2 and found to localize in the ATP-binding pocket of the kinase. Their selectivity and cellular effects have been thoroughly investigated. Following encouraging results obtained in preclinical tests and favorable pharmacological properties, one of these purines, roscovitine (CYC202), is now entering phase II clinical trials against cancers and phase I clinical tests against glomerulonephritis. CDK inhibitors are also being evaluated, at the preclinical level, for therapeutic use against neurodegenerative diseases, cardiovascular disorders, viral infections, and parasitic protozoa. This initially unexpected scope of potential applications and the large number and chemical diversity of pharmacological inhibitors of CDKs now available constitute a very encouraging stimulus to pursue the search for optimization and characterization of protein kinase inhibitors, from which we expect numerous therapeutic applications.
本文回顾了一系列研究步骤，这些步骤引领我们从利用海星卵母细胞模型对细胞分裂周期进行的基础研究，发展到如今对正在临床评估用于抗癌的药物的鉴定。在进入M期时被激活的蛋白激酶中，细胞周期蛋白依赖性激酶CDK1/细胞周期蛋白B最初被鉴定为一种通用的M期促进因子。随后它被用作筛选靶点来鉴定药理抑制剂。最早发现的抑制剂是6-二甲基氨基嘌呤和异戊烯腺嘌呤，在此基础上优化出了更有效和更具选择性的抑制剂（olomoucine、roscovitine和purvalanols）。所有这些抑制剂都与CDK2共结晶，并发现它们定位于激酶的ATP结合口袋中。对它们的选择性和细胞效应进行了深入研究。在临床前试验取得令人鼓舞的结果且具有良好的药理特性后，其中一种嘌呤类药物roscovitine（CYC202）现已进入针对癌症的II期临床试验以及针对肾小球肾炎的I期临床试验。在临床前水平上，CDK抑制剂也正在被评估用于治疗神经退行性疾病、心血管疾病、病毒感染和寄生原生动物。这种最初出人意料的潜在应用范围以及目前可用的CDK药理抑制剂的大量和化学多样性，构成了一个非常令人鼓舞的动力，促使我们继续寻找蛋白激酶抑制剂的优化和特性，我们期望从中获得众多治疗应用。
