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Abstract：
BACKGROUND: Cyclin-dependent kinase-2 (CDK-2) is an important regulatory factor in the G1/S phase transition. CDK-2 targeting has been shown to suppress the viability of multiple cancers. However, the exploration and application of a CDK-2 inhibitor in the treatment of glioblastoma are sparse.
METHODS: We synthesized P129 based on isolongifolanone, a natural product with anti-tumor activity. Network pharmacology analysis was conducted to predict the structural stability, affinity, and pharmacological and toxicological properties of P129. Binding analysis and CETSA verified the ability of P129 to target CDK-2. The effect of P129 on the biological behavior of glioma cells was analyzed by the cell counting kit-8, colony formation, flow cytometry, and other experiments. Western blotting was used to detect the expression changes of proteins involved in the cell cycle, cell apoptosis, and epithelial-mesenchymal transition.
RESULTS: Bioinformatics analysis and CETSA showed that P129 exhibited good intestinal absorption and blood-brain barrier penetrability together with high stability and affinity with CDK-2, with no developmental toxicity. The viability, proliferation, and migration of human glioma cells were significantly inhibited by P129 in a dose- and time-dependent manner. Flow cytometry and western blotting analyses showed G0/G1 arrest and lower CDK-2 expression in cells treated with P129 than in the controls. The apoptotic ratio of glioma cells increased significantly with increasing concentrations of P129 combined with karyopyknosis and karyorrhexis. Apoptosis occurred via the mitochondrial pathway.
CONCLUSIONS: The pyrazole ring-containing isolongifolanone derivate P129 exhibited promising anti-glioma activity by targeting CDK-2 and promoting apoptosis, indicating its potential importance as a new chemotherapeutic option for glioma.
METHODS: We synthesized P129 based on isolongifolanone, a natural product with anti-tumor activity. Network pharmacology analysis was conducted to predict the structural stability, affinity, and pharmacological and toxicological properties of P129. Binding analysis and CETSA verified the ability of P129 to target CDK-2. The effect of P129 on the biological behavior of glioma cells was analyzed by the cell counting kit-8, colony formation, flow cytometry, and other experiments. Western blotting was used to detect the expression changes of proteins involved in the cell cycle, cell apoptosis, and epithelial-mesenchymal transition.
RESULTS: Bioinformatics analysis and CETSA showed that P129 exhibited good intestinal absorption and blood-brain barrier penetrability together with high stability and affinity with CDK-2, with no developmental toxicity. The viability, proliferation, and migration of human glioma cells were significantly inhibited by P129 in a dose- and time-dependent manner. Flow cytometry and western blotting analyses showed G0/G1 arrest and lower CDK-2 expression in cells treated with P129 than in the controls. The apoptotic ratio of glioma cells increased significantly with increasing concentrations of P129 combined with karyopyknosis and karyorrhexis. Apoptosis occurred via the mitochondrial pathway.
CONCLUSIONS: The pyrazole ring-containing isolongifolanone derivate P129 exhibited promising anti-glioma activity by targeting CDK-2 and promoting apoptosis, indicating its potential importance as a new chemotherapeutic option for glioma.
摘要：
背景：细胞周期蛋白依赖性激酶-2（CDK-2）是G1/S相变中的重要调节因子。CDK-2靶向已显示抑制多种癌症的生存力。然而,CDK-2抑制剂在胶质母细胞瘤治疗中的应用探索较少。
方法：我们合成了P129，具有抗肿瘤活性的天然产物。进行了网络药理学分析，以预测结构稳定性，亲和力,以及P129的药理和毒理学特性。结合分析和CETSA验证了P129靶向CDK-2的能力。用细胞计数试剂盒-8分析P129对胶质瘤细胞生物学行为的影响,流式细胞术,和其他实验。免疫印迹法检测细胞周期相关蛋白的表达变化,细胞凋亡，和上皮-间质转化。
结果：生物信息学分析和CETSA显示，P129具有良好的肠道吸收和血脑屏障穿透性，稳定性和与CDK-2的亲和力高，无发育毒性。生存能力,扩散,P129以剂量和时间依赖性方式显著抑制人脑胶质瘤细胞的迁移。流式细胞术和蛋白质印迹分析显示，用P129处理的细胞中G0/G1停滞和CDK-2表达低于对照组。随着P129浓度的增加，胶质瘤细胞的凋亡率显着增加，并伴有核缩和核裂。细胞凋亡是通过线粒体途径发生的。
结论：含吡唑环的异环亚叶酸酮衍生物P129通过靶向CDK-2和促进细胞凋亡而显示出有希望的抗胶质瘤活性，表明其作为神经胶质瘤新的化疗选择的潜在重要性。
方法：我们合成了P129，具有抗肿瘤活性的天然产物。进行了网络药理学分析，以预测结构稳定性，亲和力,以及P129的药理和毒理学特性。结合分析和CETSA验证了P129靶向CDK-2的能力。用细胞计数试剂盒-8分析P129对胶质瘤细胞生物学行为的影响,流式细胞术,和其他实验。免疫印迹法检测细胞周期相关蛋白的表达变化,细胞凋亡，和上皮-间质转化。
结果：生物信息学分析和CETSA显示，P129具有良好的肠道吸收和血脑屏障穿透性，稳定性和与CDK-2的亲和力高，无发育毒性。生存能力,扩散,P129以剂量和时间依赖性方式显著抑制人脑胶质瘤细胞的迁移。流式细胞术和蛋白质印迹分析显示，用P129处理的细胞中G0/G1停滞和CDK-2表达低于对照组。随着P129浓度的增加，胶质瘤细胞的凋亡率显着增加，并伴有核缩和核裂。细胞凋亡是通过线粒体途径发生的。
结论：含吡唑环的异环亚叶酸酮衍生物P129通过靶向CDK-2和促进细胞凋亡而显示出有希望的抗胶质瘤活性，表明其作为神经胶质瘤新的化疗选择的潜在重要性。
