Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Future Med Chem. 2020 Jan;12(2):127-145. doi: 10.4155/fmc-2019-0062. Epub 2019 Nov 13.
CDK4/6 have critical roles in the early stage of the cell cycle. CDK2 acts later in the cell cycle and has a considerably broader range of protein substrates, some of which are essential for normal cell proliferation. Therefore, increasing the selectivity of cyclin-dependent kinase (CDK) inhibitors is critical. In this study, we construct a versatile, specific CDK4 pharmacophore model that not only matches well with 8119 of the reported 9349 CDK4/6 inhibitors but also differentiates from the CDK2 pharmacophore. : we demonstrate the activity and selectivity determinants of CDK4/6 selective inhibitors based on the CDK4 pharmacophore model. Finally, we propose the future optimization strategy for CDK4/6 selective inhibitors, providing a theoretical basis for further research and development of CDK4/6 selective inhibitors.
CDK4/6 在细胞周期的早期阶段发挥着关键作用。CDK2 在细胞周期的后期起作用，并且具有更广泛的蛋白质底物范围，其中一些对于正常细胞增殖是必需的。因此，提高细胞周期蛋白依赖性激酶（CDK）抑制剂的选择性至关重要。在这项研究中，我们构建了一个通用的、特异的 CDK4 药效团模型，该模型不仅与报告的 9349 种 CDK4/6 抑制剂中的 8119 种匹配良好，而且与 CDK2 药效团区分开来。我们基于 CDK4 药效团模型，展示了 CDK4/6 选择性抑制剂的活性和选择性决定因素。最后，我们提出了 CDK4/6 选择性抑制剂的未来优化策略，为进一步研究和开发 CDK4/6 选择性抑制剂提供了理论基础。
