Cyclin dependent kinases (Cdks) are essential enzymes for the control of cell cycle progression. Inhibitors of cyclin-dependent kinases are anticipated to possess therapeutic utility against a wide variety of proliferative diseases, especially cancer. The field of published small molecule Cdk inhibitors is briefly reviewed here as background to a summary of work on a class of pyrido[2,3-d]pyrimidine Cdk inhibitors. Compounds from this class are described that display potency against cyclin D/Cdk4 up to IC(50) = 0.004 microM. Good to moderate selectivity for cyclin D/Cdk4 is also reported for compounds in this structural class. Structure-activity relationship data are presented for substitution at the C2 and N8 positions and these data are interpreted in the context of a binding model that is based on the Cdk2 crystal structure. A representative cyclin D/Cdk4 inhibitor (compound 56) is demonstrated to selectively inhibit the proliferation of an Rb(+) cell line vs. a matched Rb(-) cell line and to produce a distinct G(1) block consistent with cyclin D/Cdk4 inhibition in cells.

中文翻译：

---

细胞周期蛋白依赖性激酶抑制剂，用于治疗癌症。

细胞周期蛋白依赖性激酶（Cdks）是控制细胞周期进程的重要酶。预期细胞周期蛋白依赖性激酶的抑制剂具有针对多种增生性疾病，特别是癌症的治疗用途。本文简要回顾了已发表的小分子Cdk抑制剂的领域，作为对一类吡啶并[2,3-d]嘧啶Cdk抑制剂的研究总结的背景。描述了此类化合物，其对细胞周期蛋白D / Cdk4的效能最高可达IC（50）= 0.004 microM。对于这种结构类别的化合物，对于细胞周期蛋白D / Cdk4的选择性也有良好的选择。给出了结构-活性关系数据用于在C2和N8位置进行取代，并且在基于Cdk2晶体结构的结合模型的上下文中解释了这些数据。