Lin Tony Eight, Hsu Kai-Cheng, Chou Ching-Hsuan, Tsai En-Yun, Wu Yi-Wen, Sung Tzu-Ying, Hsu Jui-Yi, Hsieh Jui-Hua, Yen Shih-Chung, Chang Yu-Wei, Pan Shiow-Lin, Huang Wei-Jan, Yang Chia-Ron
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.
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; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Biochem Pharmacol. 2025 Jul;237:116959. doi: 10.1016/j.bcp.2025.116959. Epub 2025 Apr 23.
Idiopathic Pulmonary Fibrosis (IPF) is a disease that includes inflammation and scarring of the lung tissues. Cyclin-dependent kinase 8 (CDK8) is a target of interest due to its role in inflammatory pathways. CDK8 can also modulate the TGF-β/Smad signaling associated with IPF. Herein, a structure-based virtual screening (SBVS) campaign led to the identification of three CDK8 inhibitors. Testing of candidate inhibitors in protein and cellular assays confirmed CDK8 inhibition, with the most potent inhibitor producing an IC value of 398.8 nM. Computational analysis identified pharmacological interactions that lead to CDK8 inhibition. No significant cytotoxicity was observed when the inhibitor was treated in vitro. Further results showed that the inhibitor can disrupt proteins associated with the epithelial-mesenchymal transition (EMT) and reduce cell migration. Additionally, the inhibitor can disrupt the TGF- β1/Smad signaling axis in the nucleus, potentially impacting the transcription of IPF related protein expression, when treated in cells at 5 µM. Comparisons to structures of known CDK8 inhibitors showed the identified inhibitor to be structurally novel. When tested against a panel of kinases at 1 µM, the most potent inhibitor demonstrated a favorable CDK8 selectivity profile. The identification of the CDK8 inhibitors in this study can be used in future drug design studies and as CDK8 probes to explore alternative therapeutics for IPF.
特发性肺纤维化（IPF）是一种包括肺组织炎症和瘢痕形成的疾病。细胞周期蛋白依赖性激酶8（CDK8）因其在炎症途径中的作用而成为研究热点。CDK8还可调节与IPF相关的TGF-β/Smad信号传导。在此，基于结构的虚拟筛选（SBVS）活动导致鉴定出三种CDK8抑制剂。在蛋白质和细胞试验中对候选抑制剂进行测试，证实了对CDK8的抑制作用，最有效的抑制剂产生的IC值为398.8 nM。计算分析确定了导致CDK8抑制的药理相互作用。在体外处理抑制剂时未观察到明显的细胞毒性。进一步的结果表明，该抑制剂可破坏与上皮-间质转化（EMT）相关的蛋白质并减少细胞迁移。此外，当以5 μM处理细胞时，该抑制剂可破坏细胞核中的TGF-β1/Smad信号轴，可能影响IPF相关蛋白表达的转录。与已知CDK8抑制剂的结构比较表明，所鉴定的抑制剂在结构上是新颖的。当以1 μM针对一组激酶进行测试时，最有效的抑制剂表现出良好的CDK8选择性特征。本研究中CDK8抑制剂的鉴定可用于未来的药物设计研究，并作为CDK8探针来探索IPF的替代疗法。
