Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer,Journal of Medicinal Chemistry

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Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-09 , DOI: 10.1021/acs.jmedchem.2c00947
Weijiao Chen ₁ , Minghui Ji ₁ , Hao Cheng _{1,

2} , Mingming Zheng ₁ , Fei Xia ₁ , Wenjian Min ₁ , Huanaoyu Yang ₁ , Xiao Wang ₁ , Liping Wang ₁ , Lijuan Cao ₂ , Kai Yuan ₁ , Peng Yang _{1,

3}

Affiliation

Breast cancer is the most common tumor in women, and selective cyclin-dependent kinase (CDK) 4/6 inhibitors played an important role in the treatment of breast cancer. Therefore, discovering selective CDK4/6 inhibitors with great safety and potent efficacy is beneficial for the breast cancer treatment. In our work, the lead compound 8 was identified through virtual screening; then, systematic structural optimization was conducted to afford 42, which exhibited strong inhibition on CDK4/6 and showed high selectivity among 205 kinases. 42 possessed excellent safety profiles (LD₅₀ > 5,000 mg/kg), favorable pharmacokinetic properties (F % = 43%), and potent efficacy in reducing the burden of breast cancer in vivo. In conclusion, we offered a highly selective CDK4/6 inhibitor, which could be used as a great candidate for further preclinical studies of breast cancer.

中文翻译：

用于治疗乳腺癌的选择性 CDK4/6 抑制剂的发现、优化和评估

乳腺癌是女性最常见的肿瘤，选择性细胞周期蛋白依赖性激酶（CDK）4/6抑制剂在乳腺癌的治疗中发挥了重要作用。因此，发现安全性高、疗效强的选择性CDK4/6抑制剂有利于乳腺癌的治疗。在我们的工作中，通过虚拟筛选确定了先导化合物8 ；然后，进行了系统的结构优化，得到42，它对 CDK4/6 表现出强烈的抑制作用，并在 205 种激酶中表现出高选择性。42 种具有出色的安全性（LD ₅₀ > 5,000 mg/kg）、良好的药代动力学特性（F% = 43%), 以及在减轻体内乳腺癌负担方面的有效功效。总之，我们提供了一种高选择性的 CDK4/6 抑制剂，可作为进一步乳腺癌临床前研究的理想候选药物。

更新日期：2022-11-09

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