Discovery and SARs of 5-Chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity.,Journal of Medicinal Chemistry

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Discovery and SARs of 5-Chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-12 , DOI: 10.1021/acs.jmedchem.9b02121
Yang Wang ₁ , Xing Chen ₁ , Yaoyao Yan ₁ , Xiaochen Zhu ₁ , Mingming Liu _{1,

2} , Xinhua Liu ₁

Affiliation

Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro-N⁴-phenyl-N²-(pyridin-2-yl)pyrimidine-2,4-diamine derivatives as dual CDK6 and 9 inhibitors. Intensive structural modifications lead to the identification of compound 66 as the most active dual CDK6/9 inhibitor with balancing potency against these two targets and good selectivity over CDK2. Further biological studies revealed that compound 66 was directly bound to CDK6/9, resulting in suppression of their downstream signaling pathway and inhibition of cell proliferation by blocking cell cycle progression and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse model with no obvious toxicity, indicating the promising therapeutic potential of CDK6/9 dual inhibitors for cancer treatment. Therefore, the above results are of great importance in the development of dual CDK6/9 inhibitors for cancer therapy.

中文翻译：

口服可用的5-氯-N4-苯基-N2-（吡啶-2-基）嘧啶-2,4-二胺衍生物以及具有强抗肿瘤活性的双重CDK 6和9抑制剂的发现和SAR。

细胞周期蛋白依赖性激酶（CDK）是癌症治疗的有希望的治疗靶标。在此，我们描述了我们为发现一系列5-氯-N ^4-苯基-N ^2-（吡啶-2-基）嘧啶-2,4-二胺衍生物作为双CDK6和9抑制剂而付出的努力。强烈的结构修饰导致化合物66被鉴定为最具活性的双重CDK6 / 9抑制剂，具有针对这两个靶点的平衡效能，并且具有优于CDK2的选择性。进一步的生物学研究表明，化合物66CDK6直接与CDK6 / 9结合，通过阻断细胞周期进程并诱导细胞凋亡来抑制其下游信号传导途径并抑制细胞增殖。更重要的是，化合物66在没有明显毒性的情况下显着抑制了异种移植小鼠模型中的肿瘤生长，表明CDK6 / 9双重抑制剂在癌症治疗方面具有广阔的前景。因此，以上结果在开发用于癌症治疗的双重CDK6 / 9抑制剂中非常重要。

更新日期：2020-03-12

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