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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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