Cyclin-dependent kinases (CDKs) regulate the cell cycle, apoptosis, neuronal functions, transcription, and exocytosis. The observation of CDK deregulations in various pathological situations suggests that CDK inhibitors may have a therapeutic value. In this article, we report on the identification of 6-phenyl[5H]pyrrolo[2,3-b]pyrazines (aloisines) as a novel potent CDK inhibitory scaffold. A selectivity study performed on 26 kinases shows that aloisine A is highly selective for CDK1/cyclin B, CDK2/cyclin A-E, CDK5/p25, and GSK-3 alpha/beta; the two latter enzymes have been implicated in Alzheimer's disease. Kinetic studies, as well as the resolution of a CDK2-aloisine cocrystal structure, demonstrate that aloisines act by competitive inhibition of ATP binding to the catalytic subunit of the kinase. As observed with all inhibitors reported so far, aloisine interacts with the ATP-binding pocket through two hydrogen bonds with backbone nitrogen and oxygen atoms of Leu 83. Aloisine inhibits cell proliferation by arresting cells in both G1 and G2.

中文翻译：

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Aloisines，CDK / GSK-3抑制剂的新家族。SAR研究，与CDK2结合的晶体结构，酶选择性和细胞效应。

细胞周期蛋白依赖性激酶（CDK）调节细胞周期，凋亡，神经元功能，转录和胞吐作用。在各种病理情况下对CDK失调的观察表明CDK抑制剂可能具有治疗价值。在本文中，我们报告了对6-苯基[5H]吡咯并[2,3-b]吡嗪（醛氨酸）的鉴定，它是一种新型的有效的CDK抑制性支架。对26种激酶的选择性研究表明，芦荟碱A对CDK1 /细胞周期蛋白B，CDK2 /细胞周期蛋白AE，CDK5 / p25和GSK-3 alpha / beta具有高度选择性。后两种酶与阿尔茨海默氏病有关。动力学研究，以及CDK2-aloisine共晶体结构的解析表明，aloiisines通过竞争性抑制ATP与激酶催化亚基的结合而起作用。