Hsu Jui-Yi, Hsu Kai-Cheng, Chou Ching-Hsuan, He Tzu-Ying, Lin Tony Eight, Sung Tzu-Ying, Yen Shih-Chung, Hsieh Jui-Hua, Yang Chia-Ron, Huang Wei-Jan
Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Biomed Pharmacother. 2025 Mar;184:117891. doi: 10.1016/j.biopha.2025.117891. Epub 2025 Feb 16.
Cyclin-dependent kinase 8 (CDK8) plays a crucial role in the transforming growth factor beta (TGF-β) signaling pathway, which is critical to the pathology of idiopathic pulmonary fibrosis (IPF). CDK8 promotes the epithelial-mesenchymal transition (EMT) and excessive extracellular matrix (ECM) deposition, making it a promising target for IPF treatment. This study focused on optimizing F059-1017, a previously identified CDK8 inhibitor, to enhance its potency. Through integrated structure-based modifications, a series of compounds was synthesized, and their inhibitory effects on CDK8 were tested. Results indicated that substituting with cyclopentanone significantly improved the inhibitory activity, and compound 4j demonstrated the best potency (IC = 16 nM). Notably, compared to F059-1017, its potency increased 35-fold, and kinase profiling revealed that the compound was selective for CDK8. Compound 4j inhibited the TGF-β1-induced EMT, cell migration, and morphological changes in A549 cells at a concentration of 0.1 μM and inhibited ECM and EMT protein expressions. In addition, the compound blocked TGF-β1-induced transcriptional changes and inhibited Smad3 and RNA polymerase II phosphorylation. These results highlight the potential of the optimized CDK8 inhibitor as a prospective drug for IPF treatment.
细胞周期蛋白依赖性激酶8（CDK8）在转化生长因子β（TGF-β）信号通路中起关键作用，而该信号通路对特发性肺纤维化（IPF）的病理过程至关重要。CDK8促进上皮-间质转化（EMT）和细胞外基质（ECM）过度沉积，使其成为IPF治疗的一个有前景的靶点。本研究聚焦于优化先前鉴定的CDK8抑制剂F059-1017，以增强其效力。通过基于结构的综合修饰，合成了一系列化合物，并测试了它们对CDK8的抑制作用。结果表明，用环戊酮取代可显著提高抑制活性，化合物4j表现出最佳效力（IC = 16 nM）。值得注意的是，与F059-1017相比，其效力提高了35倍，激酶谱分析表明该化合物对CDK8具有选择性。化合物4j在0.1 μM浓度下抑制TGF-β1诱导的A549细胞EMT、细胞迁移和形态变化，并抑制ECM和EMT蛋白表达。此外，该化合物阻断TGF-β1诱导的转录变化并抑制Smad3和RNA聚合酶II磷酸化。这些结果突出了优化后的CDK8抑制剂作为IPF治疗潜在药物的可能性。
