Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, J&K, 190006, India.
Department of Family and Community Medicine, Albaha University, Albaha, 65511, Kingdom of Saudi Arabia.
Med Oncol. 2022 Jul 23;39(10):158. doi: 10.1007/s12032-022-01779-9.
The CDKs are known to play a critical role in cell cycle regulation process. Among the different groups of CDKs, CDK4 overexpression/hyperactivation is found to be present in many cancers and a specific CDK4 inhibitor, palbociclib has been recently approved by the FDA against breast cancer. However, the treatment with palbociclib has shown many associated toxicities such as-anemia, thrombocytopenia, neutropenia, and febrile neutropenia and more. Despite the fact being FDA approved for only breast cancer and no other cancers and CDK4 being overexpressed in multiple cancers. Therefore, we in our study intend to screen two novel CDK4 inhibitors that show considerably less associated toxicities and greater therapeutic implications than palbociclib. We screened the compounds using Lipinski's rule, ADMET analysis and further analyzed the selected compounds using a virtual screening method called molecular docking and validated our results by MD simulation. We studied the expression patterns and prognostic significance of CDK4 across multiple carcinomas by using some database like UALCAN, cBioportal, and KM-Plotter.
CDKs 被认为在细胞周期调控过程中起着关键作用。在不同的 CDK 组中，发现 CDK4 的过表达/过度激活存在于许多癌症中，一种特定的 CDK4 抑制剂 palbociclib 最近已被 FDA 批准用于治疗乳腺癌。然而，palbociclib 的治疗已显示出许多相关的毒性，如贫血、血小板减少、中性粒细胞减少和发热性中性粒细胞减少等。尽管 palbociclib 仅被 FDA 批准用于乳腺癌，而不是其他癌症，并且 CDK4 在多种癌症中过度表达。因此，我们在研究中旨在筛选两种新型 CDK4 抑制剂，它们与 palbociclib 相比具有明显较少的相关毒性和更大的治疗意义。我们使用 Lipinski 规则、ADMET 分析筛选化合物，并使用称为分子对接的虚拟筛选方法进一步分析所选化合物，并通过 MD 模拟验证我们的结果。我们通过使用 UALCAN、cBioportal 和 KM-Plotter 等数据库研究了 CDK4 在多种癌中的表达模式和预后意义。
