The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K(i) > 10 microM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K(i) = 0.001, 0.003, and 0.001 microM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC(50) = 0.08 microM). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

中文翻译：

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发现[4-氨基-2-（1-甲磺酰基哌啶-4-基氨基）嘧啶-5-基]（2,3-二氟-6-甲氧基苯基）甲酮（R547），一种有效且选择性的细胞周期蛋白依赖性激酶抑制剂，具有显着的体内抗肿瘤活性。

细胞周期蛋白依赖性激酶（CDK）及其细胞周期蛋白伴侣是细胞周期的关键调节因子。由于在许多人类癌细胞中频繁发现CDK的失调，因此用小分子抑制CDK的药理作用可能为治疗癌症提供有效的策略。此处报道的2，4-二氨基-5-酮嘧啶6代表了一类新型的有效和ATP竞争性抑制剂，它们选择性靶向细胞周期蛋白依赖性激酶家族。该二氨基嘧啶核心在C2-氨基位置具有取代的4-哌啶部分，在C5位置具有2-甲氧基苯甲酰基已被确定为负责CDK抑制活性的关键结构。进一步的优化导致大量类似物表现出对CDK1，CDK2，和CDK4，但对大量的丝氨酸/苏氨酸和酪氨酸激酶没有活性（K（i）> 10 microM）。作为这些代表性类似物之一，化合物39（R547）具有最佳的CDK抑制活性（对于CDK1，CDK2和CDK4分别为K（i）= 0.001、0.003和0.001 microM），并且具有出色的体外细胞效价，可抑制HCT116细胞系（IC（50）= 0.08 microM）的各种人类肿瘤细胞系的生长。在这项研究中确定了与CDK2结合的X射线晶体结构39，揭示了与我们的SAR一致的结合模式。化合物39在裸鼠中的HCT116人结肠直肠肿瘤异种移植模型中显示出显着的体内功效，具有高达95％的肿瘤生长抑制作用。基于其卓越的整体形象，