Tao Jia-Hao, Ruan Ping-Lang, Zhang Jun, Zhou Yong, Guan Cha-Xiang
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.
Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, 410078, Hunan, China.
Mol Divers. 2025 Apr;29(2):1641-1653. doi: 10.1007/s11030-024-10939-0. Epub 2024 Jul 29.
Cyclin-dependent kinases (CDKs) are overexpressed in tumor cells, and their aberrant activation can promote the progression of non-small-cell lung cancer (NSCLC). We utilized structure-based virtual screening and experimental validation to screen for potential CDKs antagonists among TargetMol natural products. Molecular docking and molecular dynamics simulation results indicate that Dolastatin 10 exhibits strong interactions with multiple subtypes of CDKs (CDK1, CDK2, CDK3, CDK4, and CDK6), forming stable CDKs-Dolastatin 10 complex compounds. Furthermore, in vitro experiments demonstrate that Dolastatin 10 significantly inhibits the viability, migration, and invasion of H1299 cells in a concentration-dependent manner, arresting the cell cycle at the G2/M phase by inducing cell senescence. These findings suggest that Dolastatin 10 may serve as a potential CDKs antagonist deserving further investigation.
细胞周期蛋白依赖性激酶（CDKs）在肿瘤细胞中过度表达，其异常激活可促进非小细胞肺癌（NSCLC）的进展。我们利用基于结构的虚拟筛选和实验验证，在TargetMol天然产物中筛选潜在的CDKs拮抗剂。分子对接和分子动力学模拟结果表明，多拉司他汀10与多种CDK亚型（CDK1、CDK2、CDK3、CDK4和CDK6）表现出强烈的相互作用，形成稳定的CDKs-多拉司他汀10复合化合物。此外，体外实验表明，多拉司他汀10以浓度依赖性方式显著抑制H1299细胞的活力、迁移和侵袭，通过诱导细胞衰老将细胞周期阻滞在G2/M期。这些发现表明，多拉司他汀10可能作为一种潜在的CDKs拮抗剂值得进一步研究。
